More categories of adults are becoming eligible to receive a Covid vaccination, not just 65+ and healthcare workers. If you live in San Diego County, work with people or with food, or have substantial health problems, likely you can get one already. Specifics and wording of eligibility, while set by the state and based on federal guidelines, will very front county to county and from provider to provider, say in fine detail of documentation for job or health condition based eligibility.
San Diego County
Note that vaccination eligibility includes 50+ starting April 1st, and starting April 15th, the general population. There is a strong push, supposedly for accounting and reporting vaccine utilization, for each county to vaccinate their own residents, and you will have to show an ID, like a DL when you show-up. Vaccination is free [covered by feds], but providers will want to bill whatever insurance or coverage you may have, like MediCare, and will ask for relevant information.
California had half-a-year to prepare for getting vaccines into people. This nexus of world-wide expertise in running world’s largest networks, Google, Facebook and Amazon, has been notably unable to provide a reliable and convenient state-wide method for scheduling vaccinations.
Scheduling Vaccination
Anecdotally, major health systems, like KP, are well organized for vaccination scheduling and delivery. Outreach targets their own patients, but they will supposedly vaccinate anyone, though actual scheduling is TBD.
California state site has been unreliable, apparently under heavy load, crashing just before actually completing scheduling process. They will take your contact info and send a confirmation email, but with no follow-up as yet.
San Diego County site is voluminous and difficult to navigate, with peripheral information, like which locations are open when. Catching an available appointment has been tricky, as least during March. Anecdotally, new appointments may be released after midnight, but this may also be a time of the heavy system load. They send you to yet another site for actual scheduling, which in turn may crash, just before completing the process.
There is a map-based service through the County, for vaccination locations near you, but they may not have the most updated information, like the recent changes in North County. Start by entering your ZIP code or allow Location Services in your web browser.
Sharp in North County
Sharp healthcare system in San Diego is running the major vaccination sites for the County and is sending their own patients through it, together with general population. Lack of coverage in the San Diego North County region is notable, after the CSU San Marcos location has been closed. Sharp’s northern-most location presently is Sharp Knollwood Building, 7944 Birmingham Drive, where 805 crosses 163.
Smaller N. County locations in Oceanside and Carlsbad may also have been closed, but a new location was announced in Escondido, at North Inland First United Methodist Church, 341 Kalmia St, though contact info is TBD. Del Mar Fairgrounds drive-through location [appointments required], has experienced recent shutdowns due to vaccine shortages.
Palomar is operating a drive-through location at Escondido, appointment required.
City of San Diego is running a vaccination location in Balboa Park, but regional eligibility is TBD.
Pharmacies
Covid vaccination service by major pharmacies, already experienced in delivering annual flu vaccinations, has been solid.
CVS national site takes you to the state and county level, to see appointments at locations near you
Pizer filed with the FDA new stability data demonstrating that their vaccine can be safely stored at temperatures as high as 5°F, found in many common freezers, and on part with Moderna recommendation for storage at -5°F.
This development may well solve a large portion of the logistics challenge that was faced by many smaller pharmacies, doctors offices and rural hospitals, without an ultra-cold freezer that was indicated by Pfizer initially, capable of temperatures below ‑76ºF.
Vaccine Reduces Transmission
Israel jumped on a country-wide vaccination early and is expecting to vaccinate 3 million people with both doses of the Pfizer vaccine by the end of February. They have been collecting consistent detailed vaccination and test data across the entire healthcare system. Now they were able to document in several studies that among those fully vaccinated with two doses prevalence of asymptomatic cases was reduced by 89% and symptomatic cases by 94%, confirmed by tests.
After a single dose, in a study of vaccinating medical staff, asymptomatic cases were reduced by 75% and symptomatic by 85%, all in line with numbers published by Pfizer from their own clinical trials.
There is early indication that population-wide use of the vaccine stops the spread of the coronavirus, but more research is in order, perhaps three to six months worth, according to BioNTech, the developer of Pfizer vaccine.
However, Israel’s proposal for world-wide use of their design for a “green passport” indicating full regiment of vaccination, has met with privacy concerns in EU, specifically from Germany and Austria.
Update: Feb. 14, 2021
mRNA Vaccine Anaphylaxis in US
Based on data in the Vaccine Adverse Event Reporting System (VAERS), 66 cases of serious to severe anaphylactic reaction to the mRNA vaccines from Pfizer and Moderna and no deaths have been reported in the course of some 18 million doses being administered.
At fewer than 4 cases per million, the incidence is generally in line with the estimate of risk of anaphylaxis after all vaccines (including seasonal influenza) of 1.3 per million. With the annual risk of being struck by lightning at about 2 cases per million, this is a rather rare occurrence.
Pfizer Allergic Reactions
Note: By now some ten million individuals have been vaccinated worldwide, at least half of those with the Pfizer product. Close to two hundred thousand volunteers worldwide took part in vaccine clinical trials prior to that. To put the number and severity of incidents documented below in perspective, from CDC data on notable allergic reactions, at a level reportable to VAERS, occur approximately at a rate of 1 in 100,000, where over 3/4 of the cases had prior history of allergies, and over 1/3 a history of anaphylaxis. In comparison, a rough estimates of Covid impact averted can be made, based on disease prevalence data published to date. Just across the currently vaccinated population, several hundred thousand Covid infections will be prevented, that would have resulted in thousands upon thousands of deaths.
During December 14–23, 2020, monitoring by the Vaccine Adverse Event Reporting System detected 21 cases of anaphylaxis after administration of a reported 1,893,360 first doses of the Pfizer-BioNTech COVID-19 vaccine (11.1 cases per million doses), including 17 in persons with a documented history of allergies or allergic reactions, seven of whom had a history of anaphylaxis. The median interval from vaccine receipt to symptom onset was 13 minutes (range = 2–150 minutes). Among 20 persons with follow-up information available, all had recovered or been discharged home. Anaphylaxis is a severe, life-threatening allergic reaction that occurs rarely after vaccination.
Instances
Several specific instances of a severe or substantial allergic reaction to Pfizer vaccinations in the middle of December have been reported in the media, two in the UK and two in Alaska.
UK
In UK on Wed, Dec 9th, two workers of the National Health Service (UK state-run healthcare system) developed an anaphylactic allergic reaction after Pfizer Covid-19 vaccination. Both individuals had previous history of severe allergic reactions: 49yo woman with egg allergies and 40yo woman with allergies to several medications. Both routinely carried epinephrine (adrenaline hormone) autoinjectors [similar to EpiPen], for use in emergency situations. A third patient had a “possible allergic reaction”, but apparently did not require a follow-up.
UK Medicines and Healthcare products Regulatory Agency (MHRA) indicated that “all of those affected recovered after treatment”. It then issued a special warning to healthcare professionals that “any person with a history of immediate-onset anaphylaxis to a vaccine, medicine or food should not receive” the vaccination.
US
In Juneau, Alaska on Tue. Dec 15, two workers at Bartlett Regional Hospital developed an allergic reaction shortly after an injection with Pfizer Covid-19 vaccine. More severe of the two cases presented with anaphylaxis and she was treated with intramuscular and IV epinephrine, other steroids and antihistamines. During a two day hospitalization, the patient, who had “no previous history of allergies to vaccines”, spent the first night in the ICU, then kept another night for observation.
The second case did not exhibit anaphylaxis, “was taken to the emergency department and administered epinephrine, Pepcid and Benadryl. He felt completely back to normal within an hour and was released”.
“Both incidents were reported to the CDC’s Vaccine Adverse Event Reporting System (VAERS) database”. In response to the cases of severe allergic reactions to the vaccine, CDC issued recommendations for people who have had allergic reactions to other vaccines or other types of severe allergies.
Pfizer Warning
There is a remote chance that the Pfizer-BioNTech COVID-19 Vaccine could cause a severe allergic reaction. A severe allergic reaction would usually occur within a few minutes to one hour after getting a dose of the Pfizer-BioNTech COVID-19 Vaccine.
Signs of a severe allergic reaction can include:
Difficulty breathing
Swelling of your face and throat
A fast heartbeat
A bad rash all over your body
Dizziness and weakness
UK Precautions
Pfizer Covid-19 vaccine has “warnings and precautions” in the UK documents, for use in individuals with “acute severe febrile illness”, those “receiving anticoagulant therapy”, and “immunocompromised persons”.
There were no reproductive toxicity or fertility studies, though MHRA “raises no concerns for safety in pregnancy”. Still, “For women of childbearing age, pregnancy should be excluded before vaccination. In addition, women of childbearing age should be advised to avoid pregnancy for at least 2 months after their second dose”. Also, the vaccine “should not be used during breast-feeding”.
No drug interaction studies have been performed, including interactions with immunosuppressants and with other Covid vaccines. However, “symptomatic treatment with analgesic and/or antipyretic medicinal products [Acetaminophen (Tylenol)] may be used”.
Trials Side Effects
During clinical trials “more people experienced side effects after the second dose than after the first”. Volunteers reported: • injection site pain • tiredness • headache • muscle pain • chills • joint pain • fever • injection site swelling • injection site redness • nausea • feeling unwell • swollen lymph nodes (lymphadenopathy)
Update: Jan. 7, 2021
Quite possibly unrelated to the Pfizer Covid-19 vaccination received on Dec 18th, previously healthy 56yo Miami physician Gregory Michael, a practicing OB-GYN, has died of “hemorrhagic stroke apparently resulting from a lack of platelets” some three weeks later. The condition is known as Thrombocytopenia, a deficit in blood clotting. His wife describes that “3 days later he saw a strong set of petechiae on his feet and hands [pinpoint, round red or brown spots on the skin], which made him seek attention at the emergency room”. Dr. Michael was admitted for intensive treatment to improve his blood platelet count, but passed over two weeks later from stroke “that took his life in a matter of minutes”.
The UK has become the first country in the world to approve the Pfizer/BioNTech COVID-19 vaccine and on Dec 8, 2020 started vaccinations.
On Dec. 11, 2020, FDA issued a press release about its first EUA for the vaccine from Pfizer/BioNTech, for individuals “16 years of age and older”. The following day CDC recommended its use, and immunizations started on Dec. 14, 2020.
Highlights
Advisory Committee recommended FDA Approval of Pfizer/BioNTech COVID-19 vaccine
FDA issued the first EUA for COVID-19 vaccine, one developed by Pfizer/BioNTech
CDC ACIP recommended the use of Pfizer/BioNTech COVID-19 vaccine in persons aged ≥16 years for the prevention of COVID-19 with prioritizing healthcare workers and nursing home residents and staff for vaccination
Application for EUA
Dr. Ugur Sahin, left, and Dr. Özlem Türeci, the couple who founded BioNTech
On Nov. 20, 2020, Pfizer Inc. and BioNTech SE submitted an Emergency Use Authorization application (EUA 27034) for an investigational vaccine intended to prevent COVID-19 [Coronavirus Disease 2019], caused by SARS-CoV-2 virus.
The vaccine is based on SARS-CoV-2 spike glycoprotein (S) antigen encoded by RNA, formulated in lipid nanoparticles (LNPs). In response to the current global health crisis, the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) development has ensured the highest compliance and quality standards.
Submitted Pfizer/BioNTech COVID-19 Vaccine Briefing Document is 92 pages long and contains information on nonclinical data, clinical studies, clinical data, pharmacovigilance and pharmacoepidemiology plan, and risk/benefit assessment. Executive Summary starts on page 8, and presents a concise view of the presented body of work.
In addition to the U.S. submission, the companies initiated rolling submissions across the globe including Australia, Canada, Europe, and the U.K.
Advisory Committee Meeting
FDA has scheduled a meeting of its Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Dec. 10 to discuss the request for emergency use authorization of a COVID-19 vaccine from Pfizer/BioNTech. With intent to make the vaccine authorization process transparent, the FDA stated that the background materials will be available to the public, including the meeting agenda and committee roster, no later than two business days prior to the meeting. Also, the FDA will livestream the VRBPAC meeting on the agency’s YouTube, Facebook and Twitter channels; the meeting will also be webcast from the FDA website.
On Dec. 8, 2020, the FDA posted online the background materials for the upcoming VRBPAC meeting.
On Dec. 10, 2020, FDA Commissioner Stephen M. Hahn, M.D. made a statement about VRBPAC meeting:
The FDA recognizes that transparency and dialog are critical to building public confidence in the COVID-19 vaccine. An open discussion with this committee—available for public viewing and with public input—about the totality of the scientific evidence regarding the safety and effectiveness of Pfizer and BioNTech’s vaccine will help ensure clear public understanding of the scientific data and information that the FDA evaluates to make a decision about whether to authorize a vaccine for emergency use for the prevention of COVID-19.
VRBPAC online web conference meeting has been livestreamed and its recording is available on YouTube.
Advisory Committee Recommendation
On Dec.10, 2020, Pfizer/ BioNTech received FDA Advisory Committee vote 17 to 4 in support of the FDA granting EUA for the companies’ COVID-19 mRNA vaccine (BNT162b2). There was one member of the Committee whose vote is not included in the 17 to 4 vote decision.
FDA Advisory Committee Briefing Document presented topics for VRBPAC Discussions, FDA review of clinical and safety and effectiveness data, sponsor’s plans for continuing blinded placebo-controlled follow-up, pharmacovigilance activities, and benefit/risk assessment.
First EUA for COVID-19 Vaccine
On Dec. 11, 2020, FDA issued press release about EUA for Pfizer/BioNTech vaccine after evaluation of available safety and effectiveness data. The authorized use is for the prevention of COVID-19 for individuals 16 years of age and older. The emergency use authorization allows the Pfizer-BioNTech COVID-19 Vaccine to be distributed in the U.S.
FDA’s Pfizer/BioNTech Covid-19 Vaccine page provides links to the authorized documents:
There is a remote chance that the Pfizer-BioNTech COVID-19 Vaccine could cause a severe allergic reaction. A severe allergic reaction would usually occur within a few minutes to one hour after getting a dose of the Pfizer-BioNTech COVID-19 Vaccine. Signs of a severe allergic reaction can include:
difficulty breathing
swelling of face and throat
fast heartbeat
bad rash
dizziness and weakness
Requirements for Storage
Pfizer/BioNTech COVID-19 Vaccine US Distribution Fact Sheet describes detailed logistical plans and tools to support effective vaccine transport, storage and temperature monitoring. Specially designed, temperature-controlled thermal shippers are utilizing dry ice to maintain recommended storage temperature conditions of -70°C±10°C for up to 10 days unopened and GPS-enabled thermal sensors with a control tower to track the location and temperature of each vaccine shipment across their pre-set routes, 24 hours a day, seven days a week.
Once at the Point of Use (PoU), there are three options for storage:
Ultra-low-temperature freezers, which are commercially available and can extend shelf life for up to six months.
The Pfizer thermal shippers, in which doses will arrive, that can be used as temporary storage units by refilling with dry ice every five days for up to 30 days of storage.
Refrigeration units that are commonly available in hospitals. The vaccine can be stored for five days at refrigerated 2-8°C conditions.
Once thawed and stored under 2-8°C conditions, the vials cannot be re-frozen or stored under frozen conditions.
Fact Sheet for Healthcare Providers Administering Vaccine provides instructions to keep frozen vials between -80ºC to -60ºC (-112ºF to -76ºF) and protected from light until ready to use. Thaw and then store undiluted vials in the refrigerator [2ºC to 8ºC (35ºF to 46ºF)] for up to 5 days (120 hours). A carton of 25 vials or 195 vials may take up to 2 or 3 hours, respectively, to thaw in the refrigerator, whereas a fewer number of vials will thaw in less time. For immediate use, thaw undiluted vials at room temperature [up to 25ºC (77ºF)] for 30 minutes. Thawed vials can be handled in room light conditions. Vials must reach room temperature before dilution. Undiluted vials may be stored at room temperature for no more than 2 hours. After dilution, store vials between 2°C to 25°C (35°F to 77°F) and use within 6 hours from the time of dilution; during storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light; any vaccine remaining in vials must be discarded after 6 hours; do not refreeze.
CDC ACIP Recommendations
The Advisory Committee on Immunization Practices (ACIP) provides advice and guidance to the Director of the CDC regarding use of vaccines and related agents for control of vaccine-preventable diseases in the civilian population of the United States. Recommendations made by the ACIP are reviewed by the CDC Director and, if adopted, are published as official CDC/HHS recommendations in the Morbidity and Mortality Weekly Report (MMWR).
On Dec. 12, 2020, ACIP voted 11–0 (three recusals) in favor of the interim recommendation (see also print version) for use of Pfizer/BioNTech COVID-19 vaccine in persons aged ≥16 years for the prevention of COVID-19. Three ACIP members recused themselves because of participation in clinical trials and/or other studies involving companies producing COVID-19 vaccines.
To guide its deliberations regarding the vaccine, ACIP employed the Evidence to Recommendations (EtR) Framework using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence for outcomes related to the vaccine, rated on a scale of 1 (high certainty) to 4 (very low certainty).
From the GRADE evidence assessment, the level of certainty for the benefits of the Pfizer-BioNTech COVID-19 vaccine was type 1 (high certainty) for the prevention of symptomatic COVID-19. Evidence was type 3 (low certainty) for the estimate of prevention of COVID-19–associated hospitalization and type 4 (very low certainty) for the estimate of prevention ofdeath.
Interim Guidance
As demand is expected to exceed supply during the first months of the national COVID-19 vaccination program, ACIP recommended in interim guidance (see also print version),
1) health care personnel and 2) residents of long-term care facilities be offered COVID-19 vaccine in the initial phase of the vaccination program
In the statement published on Sunday, Dec 13, 2020, CDC director Robert R. Redfield approved the ACIP recommendation and said,
Initial COVID-19 vaccination is set to start as early as Monday, and this is the next step in our efforts to protect Americans, reduce the impact of the COVID-19 pandemic, and help restore some normalcy to our lives and our country.
ACIP will continue to review additional data as they become available; updates to recommendations or clinical considerations will be posted on the COVID-19 ACIP Vaccine Recommendations website.
Vaccine Administration
Clinical considerations, including details of administration and use in special populations (e.g., persons who are pregnant, immunocompromised or who have severe allergies) have been published on the CDC website, with an extensive section Vaccination of pregnant or lactating people. Before vaccination, the EUA Fact Sheet should be provided to recipients and caregivers. Healthcare Providers should counsel Pfizer-BioNTech COVID-19 vaccine recipients about expected systemic and local reactogenicity.
Reporting Vaccine Adverse Events
Adverse events that occur in a recipient after receipt of COVID-19 vaccine should be reported to the Vaccine Adverse Events Reporting System (VAERS). FDA requires that vaccination providers report vaccination administration errors, serious adverse events, cases of multisystem inflammatory syndrome, and cases of COVID-19 that result in hospitalization or death after administration of COVID-19 vaccine under EUA.
CDC has developed a new, voluntary smartphone-based tool, v-safe, that uses text messaging and web surveys to provide near real-time health check-ins after patients receive COVID-19 vaccination.
The CDC/v-safe call center follows up on reports to v-safe that indicate a medically significant health impact to collect additional information for completion of a VAERS report.
During COVID-19 vaccination, the healthcare provider will give you a vaccination record card (to show you when to return for your second dose of Pfizer/BioNTech COVID-19 vaccine) and v-safe information sheet with instructions on how to register and use v-safe. And v-safe will remind you to get your second COVID-19 vaccine dose if you need one.
Due to vaccine shortages seen in EU, exporting vaccines manufactured in the region has been heavily monitored starting on January 30th, on the heels of an argument with post-Brexit UK, regarding deliveries of the Oxford vaccine by AstraZeneca, from Thermo Fisher plant in Belgium. The vaccine tensions spread into already challenging situation with supplying Northern Ireland from the UK and a new regime on its border with the Republic of Ireland.
With pressure from international partners and given firm contractual obligation by the manufacturers, no vaccine shipments from the EU have been interrupted so far. J&J vaccine is manufactured at Janssen facility in Belgium, but the company performs final “fill and finish” at their plants in the US, even for doses destined for the EU.
Ngozi Okonjo-Iweala, the new head of World Trade Organization [WTO], spoke against “vaccine nationalism”, like export restrictions on needed medicines, specifically vaccines.
Update: April 12, 2021
Emergent BioSolutions of Maryland, a vaccine manufacturer with long standing ties with the US federal government, had another failure at its Baltimore plant, due to cross contamination in production of Covid-19 vaccines developed by Johnson & Johnson and by AstraZeneca, under the contract with BARDA.
Update: Feb. 14, 2021
Trial data for Johnson & Johnson vaccine, developed by their Janssen Pharmaceutical Companies, was submitted on Feb. 4th to the FDA for emergency use authorization (EUA). The FDA gave themselves full three weeks to convene an Advisory Committee meeting to review the results on Friday, Feb. 26.
J&J vaccine is notable for utilizing a relatively established non-replicating viral vector technology, which uses an inactivated adenovirus as a carrier for the recombinant SARS-CoV-2 spike (S) protein gene, and has already been successfully deployed by J&J for several other vaccines. There are no special refrigeration storage requirements, of the type that have presented a major logistics challenge for the mRNA vaccines from Pfizer and Moderna.
Only one dose is needed and no booster, to achieve 66% protection against moderate to severe COVID-19 infection, and 72% based on data from the United States. Even more impressive is complete [100%] protection against COVID-related hospitalization and death, 28 days post-vaccination, as seen during the study.
The European Medicines Agency [EMA] has announced on Feb. 8th that they expect to approve J&J vaccine by March, despite having access to the data through a rolling submissions process starting December 1st, 2020.
Update: Feb. 1st, 2021
Sanofi in a vaccine manufacturing deal with Pfizer.
Vaccine Tracker from NYT collates status of close to a hundred Covid vaccine efforts world-wide, with only two [Pfizer and Moderna] Approved [under special regimes], but eight more as Limited [early access] and another twenty in Phase 3 efficacy trials.
Update: Jan. 2, 2021
UK Prioritizing First Doses
The UK medicines regulator NHS decided on Dec. 30, 2020, that at this stage of the pandemic giving people on the priority list the first dose of vaccine will protect the greatest number of at risk people, in the shortest possible time, and will reduce mortality, severe disease and hospitalization. They advised that the second dose of both Pfizer and Oxford/AstraZeneca vaccines be administered towards the end of the recommended vaccine dosing schedule of 12 weeks.
The UK has become the first country in the world to approve the Pfizer/BioNTech COVID-19 vaccine and on on Dec 8, 2020 started vaccinations.
On Dec. 11, 2020, FDA issued a press release about its first EUA for the vaccine from Pfizer/BioNTech. The following day CDC recommended its use, and immunizations started on Dec. 14, 2020.
Moderna
Results of Phase III clinical trial were published on Dec. 30, 2020 in the New England Journal of Medicine, Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine, L. R. Baden, et al. [Funded by the Biomedical Advanced Research and Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number NCT04470427].
On Dec. 18, 2020, FDA issued a press release about EUA for COVID-19 vaccine from Moderna, their second after Pfizer. The following day CDC recommended vaccine for use, and immunization started on Dec. 21, 2020.
On Dec. 30, 2020, Oxford/AstraZeneca vaccine was authorized for emergency supply by UK regulators. The news was covered by the UK and US press. Immunization starts on Monday, Jan.4.
Johnson & Johnson
The large scale Phase 3 trial (ENSEMBLE) interim data will be available by the end of January 2021. Our earlier post covers these events in depth.
Highlights
Phase III Clinical Trials for COVID-19 vaccines are well under way, with Moderna, Pfizer, Johnson & Johnson and Oxford/AstraZeneca in the lead. Oxford/AstraZeneca and J&J trials have had pauses due to participant illness and have been resumed after investigations.
Moderna announced that its COVID-19 vaccine candidate mRNA-1273 met the primary efficacy endpoint in the first interim analysis of the Phase III COVE study with a vaccine efficacy of 94.5%.
Dosage: Moderna targets two shots 28 days apart and Pfizer has a 2 dose regimen, 21 days apart. Oxford/AstraZeneca is using two doses four weeks apart, while the J&J vaccine candidate is the only one with a single dose.
Cold Storage: Refrigeration requirements for storage by a pharmacy or a hospital vary notably between the four vaccines. Oxford/AstraZeneca and J&J vaccines candidates use non-replicating viral vector technology and can be simply refrigerated at 2°C-4°C [36°F-40°F]. Moderna and Pfizer vaccine candidates deliver a snippet of the viral messenger RNA (mRNA), encapsulated in nanoparticles made of lipids. These vaccines require freezing for storing longer than several days: Moderna at -20°C [-4°F] and Pfizer at -70°C [-94°F].
Pfizer/BioNTech Vaccine received FDA Emergency Use Authorization (EUA)
Production Goals
Operation Warp Speed chief advisor Moncef Slaoui laid out coronavirus vaccine production goals in a video interview with CNBC Television on September 21. Below is a screenshot from the video.
Congressional Hearing on COVID-19 Vaccines
On Sept. 9, NIH Director Dr. Collins testified before the U.S. Senate Committee on Health, Education, Labor, and Pension. Titled “Vaccines: Saving Lives, Ensuring Confidence, and Protecting Public Health,” a three-hour video is online. Shorter clips include Dr. Collins’s opening statement and his remarks about the pause in AstraZeneca trial.
Sanofi
Sanofi S.A, headquartered in Paris, France, is a huge multinational pharmaceutical company, among world’s largest by prescription sales. A established vaccine provider, through their Sanofi Pasteur subsidiary, they have launched an extensive program of Covid vaccine development, actually pursuing two different approaches.
Sanofi startied with a more established recombinant protein technology, currently used in their seasonal influenza vaccines, in the CpG 1018 (Dynavax) candidate. They have collaborated with GlaxoSmithKline, another pharma multinational, to develop a matching adjuvant [compound added to the vaccine to increase immune responses to the antigen, often aluminum salts].
Sanofi also initiated a separate effort with Translate Bio on mRNA vaccine candidate MRT5500, still early in Phase 1/2 trials. It uses technology somewhat similar to Pfizer and Moderna mRNA vaccines, widely deployed in the West now.
The outcome of Phase 2 Sanofi recombinant protein candidate was insufficient to justify speeding through Phase 3 trials. Neutralizing antibodies were demonstrated at adequate levels in adults 18-49 in the trial, but not in adults 60 and older. Low antibody levels were potentially due to inadequate formulation, where too small a dosage was used.
Sanofi has since reached a manufacturing agreement with Pfizer’s mRNA vaccine development partner BioNTech, to produce 100 million doses at the site in Frankfurt.
In a similar move, Novartis announced interest in a manufacturing partnership with a major Covid vaccine developer.
Oxford/AstraZeneca
Oxford/AstraZeneca launched Phase III clinical trials for its non-replicating viral vector AZD1222 vaccine in the US, UK, Brazil, South Africa and Japan, described in our earlier post. This vaccine candidate is administered as two shots, four weeks apart.
The study started in the US on Aug. 31, the study protocol was released on Sept. 17, ClinicalTrials.gov Identifier is NCT04516746.
On Sept. 9, AstraZeneca announced a voluntary temporary pause of vaccination across all trials, to allow international regulators to review safety data related to an illness that occurred during the UK trial.
According to the press, a 37-year-old woman volunteer was hospitalized on Sept. 5, having receiving her second dose of the vaccine. She had developed neurological symptoms that were diagnosed as transverse myelitis. An independent UK committee has conducted an investigation and recommended to the Medicines Health Regulatory Authority (MHRA), Britain’s equivalent of the FDA, that the trial in the UK is safe to resume. No specific information on the decision was offered, in order to protect the confidentiality of the affected participant. European regulators have begun a real-time review of the UK trial.
Another adverse event occurred in Brazil, where the health authority Anvisa was informed on Oct. 19 of a volunteer’s death. Brazilian media reports that this 28-year-old doctor has been working with acute COV2 patients and died of COVID-19 complications. An independent review committee recommended for the trial to continue, suggesting that he was in the control group and given placebo.
On Oct. 23, AstraZeneca announced that the FDA authorized the restart of the study in the US, having reviewed all safety data from trials globally. The agency plans to require researchers to inform study subjects of the adverse events and to monitor them for any related neurological symptoms. AstraZeneca resumed enrollment for the Phase III study in the US aiming at 30,000 participants.
The very first time the AstraZeneca trial in the UK was paused was in July, after the unexplained illness of a volunteer. It turned out to be a case of multiple sclerosis, unrelated to the vaccine, and the testing resumed.
Johnson & Johnson
On Sept 23, the National Institutes of Health (NIH) announced that Johnson & Johnson started enrolling adult volunteers for Phase III clinical trial of vaccine candidate JNJ-78436735 (formerly known as Ad26.COV2-S). This non-replicating viral vector vaccine was developed by researchers at the Janssen Pharmaceutical Companies of Johnson & Johnson and it aims to prevent symptomatic COVID-19, after a single dose regimen.
Named ENSEMBLE, the trial was registered at the ClinicalTrials.gov as NCT04505722, and its clinical protocol approved on Sept. 15. Up to 60,000 volunteers will be enrolled in the trial, in the United States and internationally.
On Oct. 8, J&J announced an Advance Purchase Agreement with the European Commission (EC) to supply 200 million doses of its COVID-19 vaccine to the EU Member States, following approval or authorization from regulators, with an option to secure up to 200 million additional doses. The company already reached an agreement with the US Government for 100 million doses. In addition, J&J plans to allocate up to 500 million vaccine doses to lower income countries, with delivery beginning in the middle of next year.
On Oct. 12, the clinical trial was paused due to an unexplained illness of a study participant. The independent Data Safety and Monitoring Board (DSMB) gathered immediately to review the case. After a thorough evaluation of the serious medical event experienced by this study participant, no clear cause has been identified. On Oct 23, J&J announced DSMB recommendation to resume trial recruitment. Following a consultation with the FDA, preparations to resume the trial in the United States, including submissions for approval by the Institutional Review Board, are underway now.
J&J stated that a second Phase III study with a two-dose regimen is planned to start later this year.
Moderna
On July 27, Moderna started Phase III clinical trial of its messenger RNA vaccine candidate mRNA-1273, administered in two shots, 28 days apart, and described in our earlier post.
This clinical trial (called COVE for Coronavirus Efficacy) was registered at the ClinicalTrials.gov as NCT04470427 and its clinical protocol was published on Sept. 17. As many as 30,000 volunteers have been enrolled in the trial in the United States by Oct. 22.
On Nov 16, Moderna announced that the independent, NIH-appointed Data Safety Monitoring Board (DSMB) for the Phase III study of mRNA-1273, has informed Moderna that the trial has met the statistical criteria pre-specified in the study protocol for efficacy, with a vaccine efficacy of 94.5%. The primary endpoint of the Phase 3 COVE study is based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine. This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group.
The 95 COVID-19 cases included 15 older adults (ages 65+) and 20 participants identifying as being from diverse communities (including 12 Hispanic or LatinX, 4 Black or African Americans, 3 Asian Americans and 1 multiracial).
A secondary endpoint analyzed severe cases of COVID-19 and included 11 severe cases (as defined in the study protocol) in this first interim analysis. All 11 cases occurred in the placebo group and none in the mRNA-1273 vaccinated group.
The interim analysis included a concurrent review of the available Phase III COVE study safety data by the DSMB, which did not report any significant safety concerns. Grade 3 (severe) events greater than or equal to 2% in frequency after the first dose included injection site pain (2.7%), and after the second dose included fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%) and erythema/redness at the injection site (2.0%). These adverse events were generally short-lived. These data are subject to change based on ongoing analysis of further Phase III COVE study data and final analysis.
After accumulating enough safety data, Moderna submitted its request for the EUA. On Nov. 30, 2020, FDA announced a meeting for its Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Dec. 17 to discuss second COVID-10 vaccine candidate. Our other post covers more details on the FDA authorization and CDC recommendation for use.
On Aug. 11, the US Government awarded $1.525 billion for the manufacturing and delivery of 100 million doses of mRNA-1273.
NIH Director Dr. Collins described as encouraging the early findings of the Moderna’s Phase I clinical studies in two cohorts of 20 healthy volunteers ages 56 to 70 and ages 71 and older.
Pfizer
On March 17, Pfizer Inc. (US) and BioNTech SE (Germany) announced an agreement regarding the co-development and distribution of a potential messenger RNA (modRNA) coronavirus vaccine, aimed at preventing COVID-19 infection. Initially, BioNTech developed four vaccine candidates. Phase 1/2/3 study was registered at the ClinicalTrials.gov as NCT04368728. Phase 1/2 study started on April 29, and early positive data were released on July 1.
On July 27, companies announced the start of the Phase 2/3 safety and efficacy clinical study with 30,000 participants of 12 years of age or older [stratified as 12-15, 16-55, and >55 years]. In September Pfizer released Phase 1/2/3 study protocol with objectives, estimates and endpoints. The number of participants was increased to 44,000, with the completion target of the end of November.
The modRNA vaccine candidate BTN162b2 was selected to move forward into Phase 2/3 study at a 30 µg dose level in 2 dose regimen, 21 days apart. BTN162b2 encodes an optimized SARS-CoV-2 full length spike glycoprotein (S), which is the target of virus neutralizing antibodies. The vaccine candidate recently received FDA Fast Track designation.
Additional data from the Phase 1/2 study were released on Aug. 20, and on Sept. 30 preliminary, peer-reviewed data from the ongoing German Phase 1/2 study were published in Nature.
On Oct 6, companies announced the initiation of a rolling submission to the European Medicines Agency (EMA) for BTN162b2.
At the hearing of the House Energy & Commerce Subcommittee on Oversight and Investigations, held on July 21, Mr. John Young, Chief Business Officer of Pfizer addressed lawmakers concerns regarding a possibility of price-gouging:
We didn’t accept the federal government funding solely for the reason that we wanted to be able to move as quickly as possible with our vaccine candidate into the clinic.
On July 22, the U.S. Department of Health and Human Services (HHS) and the Department of Defense (DoD) announced a $1.95 billion agreement with Pfizer Inc. for large-scale production and nationwide delivery of 100 million doses of a COVID-19 vaccine in the United States, following the vaccine’s approval by the FDA. The agreement also allows the U.S. government to acquire an additional 500 million doses. Pfizer is planning to manufacture more than 1.3 billion doses by the end of 2021.
On Nov. 9, companies announced that the vaccine candidate is 90% efficient. By that date, the Phase III clinical study of BNT162b2 has enrolled 43,538 participants and 38,955 of them have received a second dose of the vaccine candidate. After discussions with FDA it was decided to conduct the first interim efficacy analysis at a minimum of 62 cases. The actual evaluable case count was 94 and an external independent Data Monitoring Committee (DMC) performed analysis on all cases. The case split between vaccinated individuals and those who received the placebo indicated vaccine efficacy rate above 90%, at 7 days after the second dose.
This means that protection is achieved 28 days after the initiation of the vaccination, which consists of a 2-dose schedule. As the study continues, the final analysis is planned when a total of 164 confirmed COVID-19 cases have accrued and the final vaccine efficacy percentage may vary. The companies have posted an updated version of the study protocol C4591001. Safety data for the two months following the second dose of the vaccine will be available by the third week of November.
The companies are making projections to produce globally 50 million vaccine doses in 2020. Half of those may go to the US, and since each person needs two doses, about 12.5 million Americans could be vaccinated.
On Nov. 11, Pfizer/BioNTech reached an agreement to supply the EU with 200 million doses of their vaccine candidate BNT162b2 and an option to request additional 100 million doses, with deliveries anticipated to start by the end of 2020, subject to regulatory approval. The vaccine supply for the EU will be produced by BioNTech’s manufacturing sites in Germany and Pfizer’s manufacturing site in Belgium.
On Dec. 8, FDA posted online background material for the upcoming Vaccines and Related Biological Products Advisory Committee (VRBPAC) public meeting scheduled for Dec.10 from 9:00 AM to 6:00 PM to discuss Emergency Use Authorization (EUA) of the Pfizer/BioNTech COVID-19 Vaccine. Participants joined advisory committee via online conferencing, meeting recording and event materials were published online.
On Dec. 11, 2020, FDA issued the first EUA for a vaccine for the prevention of COVID-19 in individuals 16 years of age and older. The emergency use authorization allows the Pfizer/BioNTech COVID-19 Vaccine to be distributed in the U.S. Our earlier post covers more details on the FDA authorization and CDC recommendation for use.
Cold Storage
In the US, the CDC is responsible for establishing Recommendations and Guidelines for vaccine storage and handling. The COVID-19 vaccines need to be shipped and stored in cold conditions, some vaccines need to be refrigerated at 2°C – 4°C, and others need to be frozen at -20°C or kept at an ultra-cold temperature from -60°C to -80°C. This may become a real challenge for COVID-19 vaccine adoption and distribution.
Oxford/AstraZeneca vaccine need to be refrigerated at between 2°C and 4°C, rather than frozen.
J&J stated in the announcement of the Phase 3 study:
With Janssen’s AdVac® technology, the vaccine, if successful, is estimated at launch to remain stable for two years at -20 °C and at least three months at 2-8° C. This makes the vaccine candidate compatible with standard vaccine distribution channels and would not require new infrastructure to get it to the people who need it.
Both Moderna and Pfizer vaccines require colder temperatures as company representatives reported at the August 26 meeting of the Advisory Committee on Immunization Practices (ACIP).
Moderna Storage
The company initially stored their vaccine at -70°C but now targets -20°C. At the ACIP meeting, Moderna representative Dr. Jacqueline M. Miller said,
The vaccine is shipped and stored at minus 20 degrees. And then is able to be stored at the point of care at 2 to 8 degrees in refrigerator.
On Nov. 16, Moderna announcednew data showing that mRNA-1273 remains stable at 2° to 8°C (36° to 46°F), the temperature of a standard home or medical refrigerator, for 30 days. Stability testing supports this extension from an earlier estimate of 7 days.
mRNA-1273 remains stable at -20° C (-4°F) for up to six months, at refrigerated conditions for up to 30 days and at room temperature for up to 12 hours.
Pfizer Storage
Pfizer/BioNTech representative at the ACIP meeting Dr. Nicholas Kitchin called upon Brian Gleason, from Pfizer Global Manufacturing Supply, to present details on the vaccine packaging in a thermal shipper, storage and handling techniques, time limits and temperature requirements at each stage.
Pfizer/BioNTech vaccine must be stored in an Ultra-Low Temperature (ULT) freezer at -70°C ± 10°C for up to 6 months, or in a thermal shipper for up to 10 days. After opening, the thermal shipper should be replenished with dry ice. Once removed from the thermal shipper, the vaccine can be kept for up to 24 hours in a refrigerator at 2°C – 8°C or for 2 hours at room temperature after thawing.
According to a media report, Paul Mango from HHS stated that companies participating in Operation Warp Speed will see their vaccines distributed through a medical supply and distribution company McKesson:
It includes the types of storage and the transportation requirements that we believe the vaccines to have. There is one exception to this, and that is Pfizer. … Pfizer is doing its own.
The interim data for the Phase 3 Johnson & Johnson trial (ENSEMBLE) will be available by the end of January 2021. The company expects to submit an EUA application to the FDA sometime in February. While from the start J&J targeted a single-dose regimen, they are currently also running a two-dose trial.
Applications to health regulatory agencies around the world are also in progress. Notable is a rolling submissions to the EU regulator EMA that started on Dec. 1, 2020. Earlier access to the trial data by the regulator has been offered as the reason for several weeks of delay in approval by FDA of Pfizer vaccine candidate compared to UK, when looking at the very same data for the same product. It remains to be seen how soon EU actually receives approval for J&J vaccine and how they handle the Oxford candidate.
Vaccine Candidate
As soon as the genomic sequence of the novel coronavirus SARS-CoV-2 became available in January 2020, researchers at the Janssen Pharmaceutical Companies of Johnson & Johnson, headquartered in Beerse, Belgium, constructed and started testing multiple vaccine candidates. They collaborated with Beth Israel Deaconess Medical Center, a part of Harvard Medical School. Rapid development of the new vaccine candidates was made possible by the Janssen AdVac® technology platform. On March 30, Johnson & Johnson announced their vaccine candidate for COVID-19, designated Ad26.COV2.S.
AdVac® Viral Vector Platform
Prior to the development of the COVID-19 vaccine candidate, Janssen’s AdVac® was used in the development of Ebola vaccine regimen, It received in July 2020 an authorization from the European Commission for use in adults and children, and has been deployed in the Democratic Republic of Congo (DRC) and Rwanda. The AdVac® technology was also used to construct Johnson & Johnson HIV, respiratory syncytial virus (RSV) and Zika vaccine candidates. More than 75,000 individuals have been vaccinated with these to date, including people over 65 years of age, children, infants, HIV-positive adults, and pregnant women. This clinical experience suggests that AdVac®-based vaccine candidates have been well-tolerated across those populations.
How Johnson & Johnson Vaccine Works
Ad26.COV2.S vaccine is of the non-replicating viral vector type. AdVac® uses an inactivated adenovirus as a carrier (also called vector). This type of virus in the wild causes respiratory symptoms labeled as common cold. The inactivated virus vector cannot cause a cold and the protein it produces causes no harm.
For the COVID-19 vaccine candidate Ad26.COV2.S, Janssen researchers used the human adenovirus type 26 and added a recombinant SARS-CoV-2 spike (S) protein gene. The vaccine delivers the modified DNA, which makes the SARS-CoV-2 protein, an antigen that will be recognized by the body’s immune system as a key part of SARS-CoV-2 pathogen. The immune response against the antigen produces specialized immune cells and antibodies. If the pathogen invades the body at a future date, the immune cells and antibodies specific to this pathogen are produced rapidly, to stop the infection and prevent the disease.
Funding Vaccine Development
On July 21, Macaya Douoguih, M.D., M.P.H. Head of Clinical Development and Medical Affairs at Janssen Vaccines and Prevention, Johnson & Johnson testified before the U.S. House of Representatives hearings on COVID-19 vaccines:
Under our current contract with BARDA, Johnson & Johnson will receive approximately $500 million for vaccine research and development. Our agreement with BARDA supports the co-funding of vaccine research and development efforts, including preclinical, clinical development, and the production of clinical trial material.
Study in Macaques
On March 13, Johnson & Johnson announced that its Janssen Pharmaceutical Companies entered a collaboration with the Beth Israel Deaconess Medical Center (BIDMC) to support the development of a vaccine candidate for COVID-19. On July 30, Johnson & Johnson announced that in the pre-clinical studies, its lead vaccine candidate did protect against infection with SARS-CoV-2, the virus that causes COVID-19.
Their results were published in Nature and showed that a single-shot of the vaccine candidate Ad26.COV2.S elicited immune response in non-human primates (NHPs). For the study, researchers produced seven Ad26 vectors encoding different variants of the SARS-CoV-2 spike (S) protein and evaluated their immunogenicity and protective efficacy against SARS-CoV-2 challenge in rhesus macaques.
They immunized 52 adult rhesus macaques, 6-12 years old, using Ad26 vectors, with a control group of 20. Animals received a single immunization of 1011 Ad26 viral particle vectors at week 0, by the intramuscular route without adjuvant. RBD-specific binding antibodies were observed by ELISA in 31 of 32 vaccinated animals by week 2, and in all of the vaccinated animals by week 4. Neutralizing antibody (NAb) responses were assessed using both a pseudo-virus and a live virus neutralization assays, and were observed in the majority of vaccinated animals at week 2, generally increasing by week 4.
Ad26-S.PP Candidate
Median NAb titers in the Ad26-S.PP vaccinated macaques were 4-fold higher than median NAb titers in previously reported cohorts of 9 convalescent macaques and 27 convalescent humans following recovery from SARS-CoV-2 infection. The Ad26-S.PP vaccine also induced detectable S-specific IgG and IgA responses in bronchoalveolar lavage (BAL). Cellular immune responses were induced in 30 of 32 vaccinated animals at week 4.
At week 6, all animals were challenged with 105 TCID50 SARS-CoV-2, by the intranasal (IN) and intratracheal (IT) routes. All 20 controls were infected, but in contrast, animals that received Ad26-S.PP demonstrated complete protection in both the lower and upper respiratory tract, no detectable virus in BAL and only one of the animals showed a low amount of virus in nasal swabs (NS).
Partial protection was observed with the other vaccine candidates and the animals generally demonstrated reduced viral loads in NS compared with controls, but the protection was optimal with Ad26-S.PP.
In summary, a single immunization of Ad26 vector-based vaccines in rhesus macaques elicited robust NAb titers and provided complete or near-complete protection against SARS-CoV-2 challenge. Protection in both the upper and lower respiratory tracts will likely be required to prevent transmission and disease in humans. The optimal Ad26-S.PP vaccine candidate from the study, now termed Ad26.COV2.S, is being evaluated in human clinical trials.
Dan Barouch, M.D., Ph.D., Director of the Center for Virology and Vaccine Research at BIDMC and the Ragon Institute, stated
The pre-clinical data, generated in collaboration with the Johnson & Johnson team, highlights the potential of this SARS-CoV-2 vaccine candidate. Moreover, the data suggest that antibody levels may serve as a biomarker for vaccine-mediated protection.
On July 30, a peer-reviewed paper “Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques” was published in Nature. The team of authors was jointly supervised by Hanneke Schuitemaker and Dan H. Barouch. Listed in Affiliations: Beth Israel Deaconess Medical Center, Harvard Medical School, Janssen Vaccines and Prevention, Ragon Institute, MIT, University of North Carolina at Chapel Hill, Boston Children’s Hospital.
Phase 1/2a Clinical Trials
On June 18, 2020, Janssen Vaccines and Prevention posted information about the Phase II clinical trial in the ClinicalTrials.gov database under Identifier (NCT number) NCT04436276. The purpose of this randomized, parallel assignment, double-blind, placebo-controlled clinical trial is to assess the safety, reactogenicity, and immunogenicity of Ad26.COV2.S at 2 dose levels, administered intramuscularly (IM) as a single-dose or 2-dose schedule, with a single booster vaccination administered in one cohort, in over 1,000 healthy adults.
On July 30, Johnson & Johnson announced that the Phase 1/2a trial of the Ad26.COV2.S vaccine candidate started in the United States and Belgium. Planning is underway for Phase 2a studies in the Netherlands, Spain and Germany, and a Phase 1 study in Japan.
Phase 3 Clinical Trials
On August 10, Janssen Vaccines and Prevention posted information about the Phase III clinical trial (ENSEMBLE) in the ClinicalTrials.gov database under Identifier (NCT number) NCT04505722. The purpose of this randomized, double-blind, placebo-controlled clinical trial is to demonstrate the efficacy of vaccine candidate JNJ-78436735 (formerly known as Ad26.COV2.S) in the prevention of molecularly confirmed moderate to severe/critical COVID-19, as compared to placebo, in SARS-CoV-2 adult participants. The trial follows FDA Guidance on clinical study design and has well defined Primary and Secondary outcome measures. The trial clinical protocol was approved on Sept. 15. It specifies the single-dose level for Ad26.COV2.S as 5×1010 vp (virus particles) administered on day 1.
… it will be a challenge to reliably predict disease incidence rates for the timeframe for which this study is planned. We are using available data sources and, in partnership with the Massachusetts Institute of Technology, have constructed a predictive model to determine where best to set up our trial sites globally so that they are in the areas of highest viral infection when we begin the Phase 3 trials, and to identify whom to enroll in the trials considering occupational, environmental, socioeconomic, and demographic risk factors. We have also incorporated all recommendations from the recent FDA guidance related to the development and licensure of COVID-19 vaccines into our development plan.
This large-scale, pivotal, multi-country Phase III clinical trial was launched on Sept 23 with an enrollment of 60,000 volunteers across three continents in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States. It is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of a single vaccine dose versus placebo in adults 18 years old and older, including significant representation of age 60. Due to an unexplained illness of a study participant, the clinical trial was paused on Oct.12, resumed on Oct. 23, and finally fully enrolled on Dec. 17. Rolling submissions to the EU EMA started on Dec. 1, 2020.
Two Dose Trial
A separate Phase III clinical trial of the investigational Janssen COVID-19 vaccine candidate to explore a two-dose regimen was announced on Nov. 15, 2020 by the company as ENSEMBLE 2, and registered in the ClinicalTrials.gov database under NCT04614948. Participants will receive an intramuscular injection of Ad26.COV2.S vaccine or placebo on Day 1 and Day 57 [8 weeks later]. Up to 30,000 participants will be enrolled worldwide, including Belgium, Colombia, France, Germany, the Philippines, South Africa, Spain, the United Kingdom, and the United States. The ENSEMBLE and ENSEMBLE 2 trials are running in parallel.
The ENSEMBLE 2 study is likewise a randomized, double-blind, placebo-controlled clinical trial. It looks at safety and efficacy of the two-dose regimen across a similar population. The study will assess efficacy of the investigational vaccine after both the first and second dose to evaluate protection against the virus and potential incremental benefits for duration of protection with a second dose.
J&J is unique among four major vaccine development contenders in already having 3-6 months of results on the dynamics of a single dose efficacy. Once supplemented with the outcomes of a parallel large scale two dose study, their dataset will be unmatched for assessing single and two dose immunity over long intervals, by design.
Implications of dose scheduling is specifically relevant at this moment, in light of shortages of Moderna and Pfizer vaccines, where each major jurisdiction will be making critical decisions regarding prioritizing doses, with some opting to apply a single dose without delay, and a second dose postponed for months, in anticipation of higher availability.
Vaccine Storage
With Janssen’s AdVac® technology, the vaccine is estimated to remain stable for two years at -20 °C and at least three months at 2-8° C. This makes the vaccine candidate compatible with standard vaccine distribution channels and would not require new infrastructure to get it to the people who need it.
Agreements and Commitments
On August 5, Johnson & Johnson announced an agreement with the U.S. government for a large scale domestic manufacturing and delivery of 100 million doses of Ad26.COV2.S vaccine, following an approval or Emergency Use Authorization by the FDA. The Biomedical Advanced Research and Development Authority (BARDA) and U.S. Department of Defense (DoD) committed over $1 billion to this agreement. The U.S. government may purchase an additional 200 million doses of Ad26.COV2.S, under a subsequent agreement.
The vaccine for the clinical trials will be produced at Janssen’s facility in Leiden, the Netherlands. On April 23, Johnson & Johnson announced a collaboration between the Janssen Pharmaceutical and Emergent BioSolutions. to expand manufacturing of the vaccine by adding more plants in other countries. This production capability aims to supply over a billion doses globally, through the course of 2021.
On Oct. 8, 2020, Johnson & Johnson announced that the European Commission (EC), acting on behalf of the European Union (EU) Member States, has approved an Advance Purchase Agreement for the supply of 200 million doses of the COVID-19 vaccine candidate to the EU Member States. The EU Member States also have the option to secure up to 200 million additional doses.
On Dec. 18, 2020, Johnson & Johnson announced an agreement with Gavi, the Vaccine Alliance, to provide 100 million doses of Janssen’s COVID-19 vaccine candidate in 2021, with an opportunity to order another 100 million doses in 2021, and up to 300 million doses in 2022, for a combined total of up to 500 million doses through 2022.
Vaccine Cost
On March 30, Jonson & Jonson announced plans to begin production of vaccine candidate at risk immediately and is committed to bringing an affordable vaccine to the public on a not-for-profit basis, for emergency pandemic use. If the doses purchased by the U.S. government are used in a COVID-19 vaccination campaign, the vaccine would be available to the American people at no cost. As is customary with government-purchased vaccines, healthcare professionals could charge for the cost of administering the vaccine.
“Vaccine hesitancy” is defined by the World Health Organization (WHO) as a “delay in acceptance or refusal of vaccines despite availability of vaccination services”, and this phenomenon has been reported previously in many countries.
For the six months of the COVID-19 pandemic already, people are under the stress of disrupted economy, isolation, illness and death. The scientists and drug manufacturers, with the support from the federal government, are working hard to develop SARS-CoV-2 vaccines quickly. Despite the promise of vaccination, a number of Americans worry about whether SARS-CoV-2 vaccines will e safe or if they work at all. And some have been mistrustful of vaccine manufacturers, regulatory agencies or the public health authorities in the past and may opt out of the life-preserving public health measure of a COVID-19 vaccine.
Vaccine Safety Summit
For two days in December 2019, WHO conducted the Global Vaccine Safety Summit with participants from national regulatory authorities, pharmacovigilance (or drug safety) staff from all regions, immunization program managers, industry representatives and funding agencies. Produced document Global Vaccine Safety Blueprint 2.0 (GVSB2.0) defines goals of vaccine safety systems including how to better detect, report, and analyze adverse events and empower consumers with scientific information and the risks and benefits of vaccines to build vaccine confidence since
… vaccines safety profiles need to be updated continuously throughout their life cycle. Many rare vaccine reactions or individual vulnerabilities can only be ascertained through observational studies after vaccines have received regulatory approval and are in widespread use.
Centers for Disease Control and Prevention (CDC) provides information on the United States vaccine safety system and “insures that vaccines are as safe as possible. As new information and science become available, the system is updated and improved”.
Now, after the results of the first phases of SARS-CoV-2 vaccine studies were published by researchers, we can look up a few reports to see how they address vaccine safety issues.
Oxford Vaccine Animal Studies
On May 13, Oxford University scientists published a report on animal studies of the adenovirus-vectored vaccine ChAdOx1 nCoV-19 where they concluded:
We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed.
On May 15, National Institutes of Health (NIH) stated in its article that
A single dose of ChAdOx1 nCoV-19, an investigational vaccine against SARS-CoV-2, has protected six rhesus macaques from pneumonia caused by the virus, according to National Institutes of Health scientists and University of Oxford collaborators.
Oxford Vaccine Phase I/II Clinical Trial
On July 20, a preliminary report “Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a Phase 1/2, single-blind, randomized controlled trial” was published in the scientific journal, The Lancet. The study was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606.
Here is a quote from this report about the preliminary findings on safety:
Safety was assessed over 28 days after vaccination… Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomized ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05)
Note that prophylactic paracetamol is used for the prevention of fever in children receiving vaccination as part of a standard childhood immunization schedule.
Volunteer Experience
Here is how Richard Fisher describes his experience as a volunteer in this trial:
Half the volunteers will get this vaccine. The second group will be given an existing licensed vaccine called MenACWY (either Nimenrix or Menveo), which is used to protect against the causes of meningitis or sepsis. This vaccine is a “control” for comparison, and was chosen instead of an inert placebo so that the control group experience the effects (and side-effects) of a real vaccine, preventing them from working out which group they are in. Like any clinical trial, it’s necessary to ensure participants are fully aware of potential side-effects, from the mild (nausea, headaches and so on) to the rare and severe (Guillain-Barre syndrome, which causes severe weakness and can be fatal). At the screening, volunteers even had to be briefed on “theoretical concerns” that the vaccine could make the effects of coronavirus worse. Some studies on animals that received experimental vaccines to protect against SARS (a related virus) have shown worsened lung inflammation when they were infected with SARS. One report had found similar lung inflammation in vaccinated mice infected with MERS. The effect had thankfully not been seen in animal studies for the Oxford Covid-19 vaccine, however. Most of all, I felt reassured to hear that thousands of people had already received the Oxford vaccine without severe side-effects – which was confirmed by the group’s study in the Lancet journal on 20 July. (And just to be absolutely clear, none of these potential reactions should bolster the unfounded claims of anti-vax campaigners)
Moderna Vaccine Animal Studies
On July 28, Moderna, Inc. scientists published in the New England Journal of Medicine an article “Evaluation of the mPNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates”.
Twenty-four Indian-origin rhesus macaques were divided into three study groups. Animals were vaccinated intramuscularly at week 0 and at week 4 with either 10 or 100 μg of mRNA-1273 in 1 ml of 1× phosphate-buffered saline (PBS). Unvaccinated control animals were administered an equal volume of 1× PBS. To evaluate the protective efficacy of mRNA-1273, all animals were challenged with SARS-CoV-2 virus infection 4 weeks after the second vaccination. The objective was to deliver virus to both the upper and lower airways to detect levels of virus that were similar to what has been detected in nasal secretions of humans after SARS-CoV-2 infection.
Same day Moderna, Inc. announced results of this preclinical animal study quoting Stephen Hoge, M.D., President at Moderna
This important preclinical study shows that mRNA-1273 protected against a high dose SARS-CoV-2 infection in non-human primates and prevented pulmonary disease in all animals, further supporting the clinical advancement of mRNA-1273. We believe this is the first demonstration of control of viral replication within two days of challenge in both the nose and lungs in non-human primates by a vaccine against COVID-19.
Moderna Vaccine Phase I Clinical Trial
On July 14, a Phase I clinical trial preliminary report “An mRNA Vaccine against SARS-CoV-2 – Preliminary Report” was published in the scientific journal, New England Journal of Medicine. Also, Phase I clinical trial report “Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19)” was posted by the ClinicalTrials.gov with identifier (NTC number) NCT04283461,last update on July 17, 2020.
It was dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. Adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.
The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified.
Johnson & Johnson Vaccine Animal Studies
On July 30, Johnson & Johnson announced that in the pre-clinical studies, its lead vaccine candidate did protect against infection with SARS-CoV-2, the virus that causes COVID-19.
Their results were published in Nature and showed that a single-shot of the vaccine candidate Ad26.COV2.S elicited immune response in non-human primates (NHPs). For this study, researchers produced seven Ad26 vectors encoding different variants of the SARS-CoV-2 spike (S) protein and evaluated their immunogenicity and protective efficacy against SARS-CoV-2 challenge in rhesus macaques. They immunized 52 adult rhesus macaques, including control group of 20. Animals received a single immunization of 1011 viral particles (vp) Ad26 vectors by the intramuscular route without adjuvant at week 0. Neutralizing antibody (NAb) responses were observed in the majority of vaccinated animals at week 2 and generally increased by week 4. Median NAb titers in the Ad26-S.PP vaccinated macaques were 4-fold higher than median NAb titers in previously reported cohorts of 9 convalescent macaques and 27 convalescent humans following recovery from SARS-CoV-2 infection. At week 6, all animals were challenged with 1.0×105 TCID50 SARS-CoV-2 by the intranasal (IN) and intratracheal (IT) routes. All 20 controls were infected while the optimal Ad26-S.PP vaccine from this study, termed Ad26.COV2.S, provided complete or near-complete protection against SARS-CoV-2 challenge in rhesus macaques.
Results of Phase III clinical trial were published on Dec. 30, 2020 in the New England Journal of Medicine, Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine, L. R. Baden, et al. [Funded by the Biomedical Advanced Research and Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number NCT04470427].
On Dec. 18, 2020, FDA issued a press release about EUA for COVID-19 vaccine from Moderna, their second after Pfizer. The following day CDC recommended vaccine for use, and immunization started on Dec. 21, 2020.
First Month of the COVID-19 Pandemic
To understand the timeline of the Covid-19 vaccine development worldwide, one needs to look at the early history of the research. At the time nobody knew that the world was heading into COVID-19 pandemic, but by the end of February more than 82,000 people in 47 countries would became infected with the novel coronavirus, and several thousands already dead.
On January 10, 2020, the genome sequence of SARS-CoV-2 (WH-Human_1) virus from a case of a respiratory disease from the Wuhan outbreak was posted online by Edward C. Holmes, University of Sydney, on behalf of the consortium led by Professor Yong-Zhen Zhang, Fudan University, Shanghai.
Vaccine Candidate mRNA-1273
On January 13, the National Institutes of Health (NIH) and infectious disease research team from the biotechnology company Moderna Inc., Cambridge, MA finalized the sequence for vaccine candidate mRNA-1273 and started preparations for clinical manufacturing. National Institute of Allergy and Infectious Diseases (NIAID) disclosed their intent to support vaccine development and run a Phase I study; the Coalition for Epidemic Preparedness Innovations (CEPI) provided funding for the first batch of the vaccine.
On February 7, the first clinical batch was completed and submitted to analytical testing for release, and on February 24, it was shipped to NIH for use in the Phase I clinical study.
On March 4, FDA completed its review of the Investigational New Drug Application (IND) filed by the NIH for mRNA-1273 and allowed the study to proceed to clinical trials.
COVID-19 outbreak is the third coronavirus one in recent years, as the NIH Director Dr. Francis Collins, writes in his blog:
Earlier coronavirus outbreaks included SARS (severe acute respiratory syndrome), which emerged in late 2002 and disappeared two years later, and MERS (Middle East respiratory syndrome), which emerged in 2012 and continues to affect people in small numbers
Scientists from NIAID’s Dale and Betty Bumpers Vaccine Research Center (VRC) have been studying the coronaviruses by focusing on the unique spike protein crowning their surfaces and they designed a vaccine that would present the spike protein to the immune system.
3D Structural Genomics Maps
As Dr. Francis Collins continues, just in two weeks after the genome sequence for SARS-CoV-2 was posted online, NIH-funded researchers, including Jason McLellan from The University of Texas at Austin, created the first atomic-scale map of a promising protein target for vaccine development. They concluded that
this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor
McLellan Lab, University of Texas at Austin
Colorful atomic-level structure of the spike protein (green appendage) of the virus allows it to bind angiotensin-converting enzyme 2 (ACE2) receptor on human cells, causing other portions of the spike to fuse the virus to the human cell membrane.
In a later blog, Dr. Francis Collins credited the report from a team led by Qiang Zhou, Westlake Institute for Advanced Study, Hangzhou, China, for presenting:
an atomic-scale snapshot showing the 3D structure of the spike protein on thenovel coronavirus attached to a human cell surface protein called ACE2, or angiotensin-converting enzyme 2. ACE2 is the receptor that the virus uses to gain entry. What makes this image such a big deal is that it shows—in exquisite detail—how the coronavirus attaches to human cells before infecting them and making people sick. The structural map of this interaction will help guide drug developers, atom by atom, in devising safe and effective ways to treat COVID-19
Adapted from Yan R., Science, 2020.
The molecular map shows the interaction between the novel coronavirus spike protein (gold) and the peptidase domain (blue) of ACE2.
How Moderna Vaccine Works
Vaccine candidate mRNA-1273 was developed by NIAID’s VRC, in a partnership with Moderna. Dr. John Mascola, Director of VRC, described the process in an interview conducted by Dr. Francis Collins:
Our approach was a nucleic acid-based vaccine… It’s this type of vaccine that can be moved most rapidly into the clinic for initial testing. When we learned of the outbreak in Wuhan, we simply accessed the nucleic acid sequence of SARS-CoV-2, the novel coronavirus that causes COVID-19… We looked at the spike sequence and built that into an RNA vaccine. This is called in silico vaccine design. Because of our experience with the original SARS back in the 2000s, we knew its sequence and we knew this approach worked. We simply modified the vaccine design to the sequence of the spike protein of SARS-CoV-2. Literally within days, we started making the vaccine in the lab… From the time the sequence was made available in early January to the start of the first in-human study, was about 65 days.
Another informative excerpt from the transcript of the interview:
Collins: For the volunteers who enrolled in the phase 1 study, what was actually in the syringe?
Mascola: The syringe included messenger RNA (mRNA), the encoded instructions for making a specific protein, in this case the spike protein. The mRNA is formulated in a lipid nanoparticle shell. The reason is mRNA is less stable than DNA, and it doesn’t like to hang around in a test tube where enzymes can break it down. But if one formulates it just right into a nanoparticle, the mRNA is protected. Furthermore, that protective particle allows one to inject it into muscle and facilitates the uptake of the mRNA into the muscle cells. The cells translate the mRNA into spike proteins, and the immune system sees them and mounts a response.
Collins: Do muscle cells know how to take that protein and put it on their cell surfaces, where the immune system can see it?
Mascola: They do if the mRNA is engineered just the right way. We’ve been doing this with DNA for a long time. With mRNA, the advantage is that it just has to get into the cell [not into the nucleus of the cell as it does for DNA]. But it took about a decade of work to figure out how to do nucleotide silencing, which allows the cell to see the mRNA, not destroy it, and actually treat it as a normal piece of mRNA to translate into protein. Once that was figured out, it becomes pretty easy to make any specific vaccine
Moderna Funding
On April 16, Moderna announced an award from U.S. government agency Biomedical Advanced Research and Development Authority (BARDA) for up to $483 million, to accelerate the development of mRNA-1273. The award was aimed to accelerate the vaccine candidate development toward FDA licensure and manufacturing process scale-up, so as to enable 2020 large-scale production for the pandemic response.
Additional funding by BARDA, for up to $472 million to support expansion of the mRNA-1273 clinical development plan, to include 30,000 participant Phase III clinical trial, was announced on July 26, 2020, for the total of $955 million in BARDA awards to Moderna.
Separately, in May 2020 $1.3 billion was secured by Moderna from investors in the company’s most recent equity offering, to begin producing mRNA-1273 supply.
On August 11, the U.S. Department of Health and Human Services (HHS) and Department of Defense (DoD) announced an agreement to provide up to approximately $1.5 billion to Moderna, Inc. to manufacture and deliver 100 million doses of the company’s mRNA-1273 vaccine candidate. The government also can acquire up to an additional 400 million doses of the vaccine. The federal government will own these vaccine doses and make them available to the American people at no cost for the vaccine itself. As is customary with government-purchased vaccines, healthcare professionals could charge for the cost of administering the vaccine.
Phase I Clinical Trial
On March 16, NIAID announced the start of Phase I clinical trial evaluating the mRNA-1273 vaccine candidate for COVID-19. The clinical trial of mRNA-1273 was designed to assess its safety, reactogenicity and immunogenicity.
The trial was conducted at the Kaiser Permanente Washington Health Research Institute in Seattle and at the Emory University School of Medicine in Atlanta.
It was a dose-escalation, open-label trial involving 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. On the basis of the results obtained in these patients at these dose levels, additional groups of older adults (ages 56-70) and elderly adults (ages 71 and above) were added to the protocol, whose results will be reported in a subsequent publication. The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020. Adverse events occurred in more than half the participants and included fatigue, chills, headache, myalgia, and pain at the injection site.
Binding antibody responses were assessed by enzyme-linked immunosorbent assay (ELISA). T-cell responses against the spike protein were assessed by an intracellular cytokine–staining assay at the NIAID Vaccine Research Center.
The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune response in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.
For comparison of the participants’ immune response with the one induced by the SARS-CoV-2 infection, 41 convalescent serum specimens were tested.
Phase I Clinical Trial Report
On July 14, a Phase I clinical trial preliminary report “An mRNA Vaccine against SARS-CoV-2 – Preliminary Report” was published in the scientific journal, New England Journal of Medicine.
Also, Phase I clinical trial report “Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19)” was posted by the ClinicalTrials.gov with identifier (NTC number) NCT04283461, updated on July 17, 2020.
Phase II Clinical Trial
On April 27, Moderna announced that it has submitted an application to the FDA for the Phase II of mRNA-1273 clinical trial design and has received an initial feedback.
This clinical trial was designed to evaluate further the safety, reactogenicity and immunogenicity after two vaccinations with mRNA-1273, given 28 days apart. Each subject will receive either placebo, a 50 μg or a 250 μg dose in both vaccinations. The company enrolled 600 healthy participants across two cohorts, adults ages 18-55 years (n=300) and older adults ages 55 and older (n=300). The first participants in the Phase II clinical trial were dosed on May 29. Participants will be followed for 12 months, after the second vaccination is delivered.
Phase II Clinical Trial Report
Report on Phase II trial was posted by the ClinicalTrials.gov NCT04405076 – “Dose-Confirmation Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1273 COVID-19 Vaccine in Adults Aged 18 Years and Older”, updated July 10, 2020.
Phase III Clinical Trial
On July 27, NIH announced the start of the Phase III clinical trial of mRNA-1273 vaccine candidate called COVE for Coronavirus Efficacy. The Phase III protocol has been reviewed by the FDA and published on Sept 17.
It is a randomized, stratified, observer-blind, placebo-controlled study to evaluate the efficacy, safety, and immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in 30,000 adults, aged 18 years and older. On Oct. 22, the enrollment in the US was completed. In line with the classic approach of giving half of the participants placebo and the other half the vaccine, participants receive either 1 intramuscular (IM) injection of 100 μg mRNA-1273 or of matching placebo, on Day 1 and then on Day 29. The 100 μg level has been selected as the optimal dose to maximize the immune response while minimizing adverse reactions.
The primary endpoint of the study will be the prevention of symptomatic COVID-19 disease. Key secondary endpoints include the prevention of severe COVID-19 disease (as defined by the need for hospitalization) and prevention of infection by SARS-CoV-2.
On Nov 16, Moderna announced that the independent, NIH-appointed Data Safety Monitoring Board (DSMB) for the Phase III study of mRNA-1273, has informed Moderna that the trial has met the statistical criteria pre-specified in the study protocol for efficacy, with a vaccine efficacy of 94.5%. The primary endpoint of the Phase III COVE study is based on the analysis of 95 COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine. Of those 95 cases, 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.5%.
A secondary endpoint analyzed severe cases of COVID-19 and included 11 severe cases (as defined in the study protocol) in this first interim analysis. All 11 cases occurred in the placebo group and none in the mRNA-1273 vaccinated group.
On Nov. 30. Moderna announced that the primary efficacy analysis of the Phase 3 study of mRNA-1273 conducted on 196 cases confirms the high efficacy observed at the first interim analysis. The data analysis indicates a vaccine efficacy of 94.1%. Today’s primary analysis was based on 196 cases, of which 185 cases of COVID-19 were observed in the placebo group versus 11 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.1%. A secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273 vaccinated group. There was one COVID-19-related death in the study to date, which occurred in the placebo group.
Also, on November 30, Moderna submitted a request for an Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) and conditional approval from the European Medicines Agency (EMA) and FDA announced Advisory Committee Meeting to Discuss Second COVID-19 Vaccine Candidate.
Phase III Clinical Trial Report
Report on Phase III trial was posted by the ClinicalTrials.gov NCT04470427“A Study to Evaluate Efficacy, Safety, and Immunogenicity of mRNA-1273 Vaccine in Adults Aged 18 Years and Older to Prevent COVID-19”, updated October 28, 2020.
Phase II/III Study in Adolescents
On Dec. 10, 2020, the company announced that the first adolescent participants have been dosed in the Phase 2/3 study of mRNA-1273, the Company’s vaccine candidate against COVID-19, in adolescents ages 12 to less than 18. The Company intends to enroll 3,000 adolescent participants in the U.S. Each participant will be assigned to receive a placebo or two vaccinations with 100 μg dose of mRNA-1273 28 days apart. The ClinicalTrials.gov identifier is NCT04649151.
Prior to the VRBPAC meeting, Moderna submitted an application for EUA, a briefing document and an addendum. VRBPAC’s online web conference meeting has been live-streamed and its recording is available on YouTube. Moderna received FDA Advisory Committee Vote (20:0 and 1 abstained) supporting emergency use for its vaccine against COVID-19 in the United States.
FDA Briefing Document describes topics for VRBPAC discussion, including vaccine composition and dosing, an overview of clinical studies, primary and secondary efficacy endpoints, phase 3 follow-up duration, participants and demographic characteristics.
On Dec. 18, 2020, FDA issued a press release about EUA for the second vaccine for the prevention of COVID-19 This EUA allows the Moderna COVID-19 Vaccine to be distributed in the U.S. for use in individuals 18 years of age and older.
FDA’s Moderna Covid-19 Vaccine page provides links to the authorized documents:
general side effects: headache, muscle pain, joint pain, chills, nausea and vomiting, and fever,
injection site reactions: pain, tenderness and swelling of the lymph nodes in the same arm of the injection, swelling (hardness), and redness.
Also, there is a remote chance that the Moderna COVID-19 Vaccine could cause a severe allergic reaction within a few minutes to one hour after getting a dose. Signs of a severe allergic reaction can include:
Difficulty breathing
Swelling of your face and throat
A fast heartbeat
A bad rash all over your body
Dizziness and weakness
CDC ACIP Recommendations
On December 19, 2020, after a review of transparent, evidence-based data CDC Advisory Committee on Immunization Practices (ACIP) voted 11–0 in favor of the interim recommendation for use of the Moderna COVID-19 vaccine in persons aged over 18 years for the prevention of COVID-19. Three ACIP members recused themselves because of participation in clinical trials and/or other studies involving companies producing COVID-19 vaccines.
To guide its deliberations regarding the vaccine, ACIP Evidence to Recommendations for Use of Moderna COVID-19 Vaccine under an Emergency Use Authorization employed the Evidence to Recommendations (EtR) Framework using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence for outcomes related to the vaccine. Section “Benefits and Harms” of this document concludes
For the critical outcomes, the certainty of evidence was high for prevention of symptomatic COVID-19, moderate for prevention of hospitalizations due to COVID-19, and moderate for serious adverse events. For important outcomes, the certainty of evidence was very low for prevention of all-cause death and prevention of asymptomatic SARS-CoV-2 infection, and high for reactogenicity
Recommendation made by ACIP was approved by the CDC Director Robert R. Redfield.
On Dec.20, 2020, it was published as official CDC/HHS recommendations in the Morbidity and Mortality Weekly Report (MMWR).
In the U.S., immunization using the Moderna COVID-19 vaccine started Monday, Dec. 21, 2020.
Vaccine Allocation
On Dec. 22, 2020 ACIP published Updated Interim Recommendation for Allocation of COVID-19 Vaccine. Previously, ACIP recommended that health care personnel and long-term care facility residents be offered COVID-19 vaccination first (Phase 1a). Updated recommendations added Phases 1b and 1c. In Phase 1b, COVID-19 vaccine should be offered to persons aged ≥75 years and non–health care frontline essential workers, and in Phase 1c, to persons aged 65–74 years, persons aged 16–64 years with high-risk medical conditions, and essential workers not included in Phase 1b.
Vaccine Administration
Vaccination with the Moderna COVID-19 vaccine consists of 2 doses (100 μg, 0.5 mL each) administered intramuscularly, 1 month (4 weeks) apart. Interim findings from the Phase III clinical trial, using data from participants with a median of 2 months of follow-up, indicating that the Moderna COVID-19 vaccine efficacy after 2 doses was 94.1% (95% confidence interval = 89.3%–96.8%) in preventing symptomatic, laboratory-confirmed COVID-19 among persons without evidence of previous SARS-CoV-2 infection.
Additional clinical considerations include details of administration and use in special populations (e.g., persons who are pregnant, immunocompromised or who have a history of severe allergic reactions)
In the U.S., immunization using COVID-19 vaccine started Monday, Dec. 21, 2020.
Progress Towards Vaccine Manufacturing
The Company remains on track to deliver approximately 500 million doses of mRNA-1273 per year, and possibly up to 1 billion doses per year, beginning in 2021. Moderna’s internal U.S. manufacturing site capacity will be augmented through a 10-year collaboration agreement with a Swiss-based drug maker Lonza, Ltd. Lonza’s experience in scaling manufacturing of innovative medicines and support for more than 50 commercial approvals across regulatory jurisdictions, will give Moderna a path to provide a global supply.
On June 25, Moderna announced a collaboration with Catalent, Inc. for large-scale, commercial fill-finish manufacturing of mRNA-1273 at Catalent’s biologics facility in Indiana. Catalent will provide vial filling and packaging capacity and additional staffing required for 24×7 manufacturing operations at the site, to support production of the initial 100 million doses of the vaccine for the U.S. market, starting in the third quarter of 2020.
Cold Storage
Moderna initially stored their vaccine at -70°C (-94°F). On Nov. 16, Moderna announced new data showing that mRNA-1273, its COVID-19 vaccine candidate, remains stable at 2° to 8°C (36° to 46°F), the temperature of a standard home or medical refrigerator, for 30 days. Stability testing supports this extension from an earlier estimate of 7 days.
mRNA-1273 remains stable at -20° C (-4°F) for up to six months, at refrigerated conditions for up to 30 days and at room temperature for up to 12 hours.
Shipping & Long-term Storage: For shipping and longer-term storage, Moderna expects that mRNA-1273 will be maintained at -20°C (-4°F).
Refrigeration Storage: After thawing, to facilitate storage at points of administration, Moderna expects that mRNA-1273 will remain stable at standard refrigerated conditions of 2° to 8°C (36° to 46°F) for up to 30 days within the 6-month shelf life.
Room Temperature for Vaccination: Once the vaccine is removed from the refrigerator for administration, it can be kept at room temperature conditions for up to 12 hours.
No Dilution Required at Vaccination Site: The vaccine will not require onsite dilution or special handling.
Vaccine Cost
On July 21, Dr. Stephen Hoge, President of Moderna, Inc. testified at the House Committee on Energy and Commerce hearings, as a representative of a company participating in the Operation Warp Speed. During questioning, he would not commit Moderna to sell their vaccine “at cost”, without realizing a profit.
Moderna’s CEO StéphaneBancel said during Aug 5 investor conference call to discuss the company’s second-quarter financial results, that smaller volume agreements with some foreign countries are executed at $32-37/dose. Larger volume agreements are under discussion, with lower prices for higher volumes.
On August 11, Moderna announced a $1.525 billion award from the US government for the manufacturing and delivery of 100 million doses of mRNA-1273 vaccine candidate. With the previous awards of $955 million from BARDA it brings US government commitment to $2.48 billion which means that the price of the vaccine is $25 per dose. The federal government will make vaccine available to the American people at no cost.
Rolling Reviews in Europe
On Nov. 13, Moderna announced that Swissmedic has started a rolling review of mRNA-1273 in consideration of a potential authorization for use of the vaccine candidate in Switzerland by Swissmedic, provided it meets Swissmedic’s rigorous standards of safety, effectiveness, and quality standards. On Nov. 17, Moderna announced a supply agreement with the UK government to supply its COVID-19 vaccine candidate beginning in March 2012 if it is approved for use by UK regulatory authorities. On Oct. 27, Moderna received confirmation that the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom started the rolling review process of mRNA-1273. On Nov. 17, Moderna announced that the European Medicines Agency (EMA) human medicines committee (CHMP) has started a rolling review of mRNA-1273, following the confirmation of eligibility of mRNA-1273 for submission on October 14, 2020.
Supply Agreements
CANADA: on Dec 7, 2020, the Canadian Government has increased its confirmed order commitment up to 40 million doses of Moderna’s vaccine against COVID-19. On Dec 23, 2020, Health Canada has authorized Moderna’s vaccine against COVID-19 for the immunization of people 18 years of age and older under an Interim Order.
QATAR: on Oct. 26, 2020, Moderna announced a supply agreement with the Ministry of Public Health of Qatar for mRNA-1273, Moderna’s vaccine against COVID-19, to support the Ministry’s ongoing efforts to secure early access to a safe and effective COVID-19 vaccine for the people of Qatar.
JAPAN: on Oct. 29, 2020, the Ministry of Health, Labor and Welfare of Japan (MHLW) and Takeda Pharmaceutical Co., have agreed to purchase and distribute 50 million doses of mRNA-1273 during the first half of 2021.
UK: on Nov. 29, 2020, Moderna announced a supply agreement with the government of the United Kingdom to supply 7 million doses its COVID-19 vaccine, beginning in March 2021.
European Commission: on Dec. 18, 2020, Moderna announced that the European Commission has exercised its option to purchase an additional 80 million doses of COVID-19 vaccine, bringing its confirmed order commitment to 160 million doses.
ISRAEL: on Dec. 4, 2020, Moderna announced that the Israeli government has now secured 6 million doses of COVID-19 vaccine. The Company has already initiated the rolling regulatory review process with the Ministry of Health in Israel.
Switzerland: on Dec. 8, 2020, the Swiss Federal Government has increased its confirmed order commitment from 4.5 million to 7.5 million doses of Moderna’s vaccine against COVID-19, following regulatory approval by Swiss health authorities. The Company has already initiated the rolling review process with Swissmedic and intends to seek Prequalification (PQ) and/or Emergency Use Listing (EUL) with the World Health Organization (WHO). Swiss vaccine supply will be sourced from Moderna’s European production capacity with its strategic manufacturing partner Lonza of Switzerland, and ROVI of Spain for fill-finish services.
SINGAPORE: on Dec. 14, 2020, the Company concluded an agreement with the Ministry of Health of Singapore to supply Moderna’s vaccine against COVID-19.
South Korea: on Dec. 29, 2020, the Company confirmed discussions with the government of South Korea to potentially provide 40 million or more doses of the Moderna COVID-19 Vaccine. Under the terms of the proposed agreement, the distribution would begin in the second quarter of 2021.
Moderna Vaccine Platform
To date, Moderna, Inc. has disclosed twenty-four therapeutic and vaccine development programs. These programs span a wide range of conditions, including infectious diseases, immuno-oncology, rare diseases, autoimmune and cardiovascular diseases. Moderna’s scientists designed its prophylactic vaccines modality to prevent a multitude of infectious diseases. The component that changes from one potential mRNA vaccine to another is the coding region – the actual genetic code that instructs ribosomes to make a specific protein. Selecting such an instruction set gives the investigational mRNA biologicals a software-like quality.
The potential advantages of an mRNA approach to prophylactic vaccines include the ability to combine multiple mRNAs into a single vaccine. More than 1,900 participants have been enrolled in Moderna’s infectious disease vaccine clinical studies, under health authorities in the U.S., Europe and Australia. Clinical Phase I studies demonstrate that Moderna’s proprietary vaccine technology has been generally well-tolerated and can elicit durable immune responses to viral antigens. Moderna has built a fully integrated manufacturing plant for its technology platform.
Reports earlier in March of dangerous blood clotting, after administration of Vaxzevria, the Oxford AstraZeneca Covid vaccine, have prompted several European countries, including Italy, Norway and Denmark, to pause using AstraZeneca in their vaccination programs.
PRAC, EMA’s safety committee has reviewed “30 cases of thromboembolic events” reported among some 5 million initial AstraZeneca vaccinations in the European Economic Area. These included instances of pulmonary embolism [blood clots in the lungs], deep vein thrombosis – DVT [legs], disseminated intravascular coagulation – DIC [throughout the body], and central venous sinus thrombosis – CVST [brain]. Most reports of DIC and CVST occurred in women under 55. PRAC since concluded “that the vaccine is not associated with an increase in the overall risk“.
Most European countries, including Germany, France and Italy, have since resumed vaccinating with the AstraZeneca, even though scientists in Germany and in Norway have offered a hypothesis that the vaccine could be triggering an autoimmune reaction that can cause blood clots. The company pointed out that over 17 million doses have already been administered in EU and UK, and that their data shows “no evidence of an increased risk of pulmonary embolism, deep vein thrombosis (DVT) or thrombocytopenia“.
AstraZeneca experienced delays in ramping up the volume of production and shipment of vaccines and potentially slowed down the vaccination campaign throughout Europe. Initially contracted to deliver 90 million doses in Q1 2021 and 180 million in Q2, AstraZeneca only managed 30 million in Q1 and expects 70 million in Q2.
AstraZeneca and Oxford collaboration on Covid vaccine development has a history of miscommunication. Most recently they came under fire in early March, for submitting efficacy data that turned out to only include case histories through mid-Feb. Results provided later in the month and aggregating all the cases produced an efficacy number somewhat smaller that the first, but still well above the minimum FDA threshold of 50% efficacy.
On Dec. 30, 2020, Oxford/AstraZeneca vaccine was authorized for emergency supply by UK regulators. The news was covered by the UK and US press. Immunization starts on Monday, Jan.4.
Oxford University and AstraZeneca
On April 30, 2020 AstraZeneca, a British-Swedish multinational pharmaceutical company and Oxford University announced an agreement for the global development and distribution of the University’s vaccine for COVID-19, aimed at preventing infection by SARS-CoV-2 virus. Vaccine is developed by the Oxford University Jenner Institute and Oxford Vaccine Group. AstraZeneca is responsible for the worldwide manufacturing and distribution of the vaccine.
Vaccine Type
The University of Oxford Jenner Institute and Oxford Vaccine Group have been developing important vaccines for many years, including one in response to the Ebola outbreak in 2014. The scientists used ChAdOx1 non-replicating viral vector vaccine technology to produce candidate vaccines against flu, Zika and Middle East Respiratory Syndrome (MERS) coronavirus. As soon as the genetic sequence of the SARS-CoV-2 virus became available in January 2020, Oxford scientists started working on COVID-19 vaccine candidate, designated AZD1222 (also known as ChAdOx1 nCoV-19).
How Oxford Vaccine Works
The ChAdOx1 vaccine starts with a chimpanzee adenovirus that can cause a common cold in chimpanzees. It has been further genetically modified to make it unable to replicate in humans. The adenovirus is well studies and used safely in thousands of subjects.
Coronavirus has a distinctive club-shaped spike protein structure on its surface. The Oxford vaccine contains the genetic sequence for this surface spike protein. When the vaccine enters human cells, this genetic code produces the surface spike protein of the coronavirus. Body’s immune system learns to produce antibodies in response to the presence of the spike protein, and if infected by the coronavirus in the future is prepared to fight it off quickly.
This colorful diagram illustrates how the Oxford COVID-19 vaccine works. A chimpanzee adenovirus is turned into the ChAdOx1 viral vector, then engineered to produce the SARS-CoV-2 spike protein.
Funding
On May 17, the UK government announced £84 million in funding for the scientists at the University of Oxford and at Imperial College London, in support of the development of the COVID-19 vaccine.
Coalition for Epidemic Preparedness Innovations (CEPI) expanded the investment in COVID-19 vaccine R&D by $23.7 million.
GAVI, the Vaccine Alliance signed a Memorandum of Understanding with AstraZeneca that guarantees purchase of 300 million doses of the COVID-19 vaccine.
On May 21, U.S. Operation Warp Speedannounced public-private partnership agreement between AstraZeneca and the US Biomedical Advanced Research and Development Authority (BARDA). BARDA will provide up to $1.2 billion to support advanced clinical studies, vaccine manufacturing technology transfer, process development, and scaled-up manufacturing at BARDA’s Centers for Innovation and Advanced Development in Manufacturing (CIADM) in the United States.
Phase I/II Clinical Trial
Phase I/II clinical trial of Oxford’s AZD1222 vaccine candidate aimed to assess safety, immunogenicity, and efficacy in over a thousand volunteers across five trial centers in southern England. AstraZeneca recognized that the vaccine may not work, but was committed to progress the clinical program and scale up manufacturing.
This single-blind, randomized controlled clinical trial included healthy adults aged 18–55 and with no history of laboratory-confirmed SARS-CoV-2 infection or of COVID-19-like symptoms. Between April 23 and May 21, 2020, 1077 participants were randomly assigned to receive a single intramuscular injection either ChAdOx1 nCoV-19 at a dose of 5 × 10^10 viral particles or of MenACWY (placebo).
Ten participants assigned to a non-randomized, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. This trial revealed that coronavirus vaccine produces strong immune response.
The vaccine provoked within 14 days of vaccination a T cell response (white blood cells that can attack cells infected with the SARS-CoV-2 virus), and an antibody response within 28 days (antibodies are able to neutralize the virus so that it cannot infect cells when initially contracted).
Clinical Trial Report
On July 20, a preliminary report “Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a Phase 1/2, single-blind, randomized controlled trial” was published in the premier UK clinical and scientific journal, The Lancet. The study was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606.
Professor Andrew Pollard, Chief investigator of the Oxford Vaccine Trial at Oxford University and co-author of the study said:
The Phase I/II data for our coronavirus vaccine shows that the vaccine did not lead to any unexpected reactions and had a similar safety profile to previous vaccines of this type. The immune responses observed following vaccination are in line with what previous animal studies have shown are associated with protection against the SARS-CoV-2 virus, although we must continue with our rigorous clinical trial program to confirm this in humans.We saw the strongest immune response in the 10 participants who received two doses of the vaccine, indicating that this might be a good strategy for vaccination.
One of the volunteers wrote about his experience at this trial.
Phase III Clinical Trials
US Phase III clinical trial of the Oxford vaccine candidate is being conducted this summer with approximately 30,000 volunteers at 33 sites in the United States.
UK Phase III clinical trial has started with 8000 volunteers.
Phase III clinical trials are also being conducted in low-to-middle income countries, including Brazil, South Africa and India.
Our other post has more information on the Phase III clinical trials.
Agreements and Commitments
AstraZeneca will produce up to 30 million doses available by September for people in the UK, as part of an agreement to deliver 100 million doses in total.
Under the Operation Warp Speed, AstraZeneca will make available at least 300 million doses of a coronavirus vaccine AZD1222 for people in US, with the first doses delivered as early as October 2020.
AstraZeneca guaranteed 300 million doses to the GAVI Vaccine Alliance for low income countries.
So far, commitments to supply more than 2 billion doses of the Oxford vaccine during 2020 and 2021 have been made with the governments of UK and US, Europe’s Inclusive Vaccines Alliance (IVA), the Coalition for Epidemic Preparedness (CEPI), and GAVI Vaccine Alliance.
AstraZeneca reached a deal with Chinese firm BioKangtai for exclusive clinical development, production and commercialization rights to the AZD1222 vaccine in China, in return BioKangtai will make 100 million doses by the end of 2020 and 200 million doses per year by the end of 2021. AstraZeneca signed a manufacturing and distribution agreement with R-Pharm in Russia. Serum Institute of India has a manufacturing arrangement with AstraZeneca to produce a billion dozes to supply vaccine to low and middle income countries. In addition, South Korea’s SK Bioscience will start producing undiluted solutions of the vaccine and Japan will order 120 million doses, beginning with 30 million doses by March next year.
Vaccine Cost
On July 21, Sir Menelas Pangolas, Ph.D., Executive Vice President of AstraZeneca testified before the U.S. House of Representatives at the hearings on COVID-19 vaccines:
To support our goal of providing broad and equitable access as quickly as possible, we have entered into agreements with the United States and certain other governments and organizations, for supply of hundreds of millions of doses of our vaccine. The cost of the doses of the vaccine under those agreements will provide no profit for AstraZeneca.
COVID-19 was first reported in Wuhan, China, in December 2019. By March 2020, when it moved rapidly through Europe and the US, most researchers and regulators from around the world agreed that cooperative effort is needed to contain this infection. Soon it became apparent that coordination among important participants in development of vaccines and therapeutics was lacking. As stated in JAMA article by the NIH Director Francis S Collins, MD, PhD and Paul Stoffels, MD:
In the US, there was no true overarching national process in either the public or private sector to prioritize candidate therapeutic agents or vaccines, and no efforts were underway to develop a clear inventory of clinical trial capacity that could be brought to bear on this public health emergency. Many key factors had to change if COVID-19 was to be addressed effectively in a relatively short time frame.
On April 3, the Foundation for the National Institutes of Health (FNIH) initiated meetings with many leaders from the national health institutes, biopharmaceutical firms, and academic experts from the US and Europe. These discussions resulted in a decision to form a public-private partnership for the development and deployment of therapeutics and vaccines for COVID-19.
ACTIV
On April 17, the NIH-led Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership was formally announced. ACTIV government and industry partners will provide infrastructure, subject matter expertise and funding to identify, prioritize and facilitate the entry of some of the most promising candidates into clinical trials.
Participating Organizations
Government: National Institutes of Health, HHS Office of the Assistant Secretary for Preparedness and Response, U.S. Food and Drug Administration, Centers For Disease and Prevention, European Medicines Agency.
Non-Profit: Foundation for the National Institutes of Health
Industry: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Evotec, GalaxoSmithKline, Johnson & Johnson, KSQ Therapeutics, Eli Lilly and Company, Merk & Co., Inc., Novartis, Pfizer, Roche, Sanofi, Takeda, Vir Biotechnology.
Four fast-track focus areas, each of which is led by a working group of senior scientists representing government, industry, and academia:
Standardize and share preclinical evaluation methods in an open forum that allows for comparison and validation
Prioritize and accelerate clinical evaluation of therapeutic candidates with near-term potential
Maximize clinical trial capacity and effectiveness
Advance vaccine development
Announcing Operation Warp Speed
On May 15, the National program Operation Warp Speed (OWS) was announced. OWS aims to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics (medical countermeasures) and have substantial quantities of a safe and effective vaccine available for Americans by January 2021.
Components of Operation Warp Speed: OWS is a public-private partnership between components of HHS, including CDC, FDA, NIH, and the Biomedical Advanced Research and Development Authority (BARDA); the Department of Defense; private firms; and other federal agencies, including the Department of Agriculture, the Department of Energy, and the Department of Veterans Affairs. OWS will coordinate existing HHS-wide efforts, including the NIH’s ACTIV partnership for vaccine and therapeutic development, NIH’s RADx initiative for diagnostic development, and work by BARDA.
Financial resources: Congress has directed almost $10 billion to this effort through supplemental funding, including the CARES Act. Over $6.5 billion has been designated by Congress for countermeasure development through BARDA, along with $3 billion for NIH research.
Development:
Select the most promising countermeasure candidates and provide coordinated government support for their development.
Align protocols for the demonstration of safety and efficacy to allow trials to proceed more quickly.
The protocols for the trials will be overseen and set by the federal government, as opposed to traditional public-private partnerships, in which pharmaceutical companies decide on their own protocols.
Manufacturing:
The federal government is making investments in manufacturing and distribution at its own risk much earlier than usual, giving firms confidence that they can invest aggressively in development of countermeasures.
Manufacturing capacity for selected candidates, including the three to five selected vaccines, will be advanced while they are still in development, rather than scaled up after approval or authorization, as is the case with traditional development timelines.
The manufacturing capacity developed will be used, to the extent practicable, for whatever vaccine is eventually successful, regardless of which firms have developed the capacity.
Distribution:
Before the countermeasures are approved or authorized, the program will build the necessary plans and infrastructure for distributing them, especially the unprecedented effort that will be necessary to deliver a vaccine to hundreds of millions of Americans in a timely manner.
OWS will also focus on expanding the supplies of specialized materials and resources, such as cold-chain storage, glass vials, and other materials, that can be necessary for distribution of countermeasures.
Once a product such as a vaccine is ready, the Department of Defense’s involvement will enable faster distribution and administration than would have otherwise been possible using wholly private medical infrastructure.
Fourteen promising candidates have been chosen from the 100+ vaccine candidates
The 14 vaccine candidates are being narrowed down to about seven candidates
March 30: HHS announced $456 million in funds for Johnson & Johnson’s candidate vaccine
April 13: HHS made $483 million available for Moderna’s candidate vaccine
May 21: HHS announced up to $1.2 billion in support for AstraZeneca’s candidate vaccine, developed in conjunction with the University of Oxford.
May 21, April 16, and March 30: HHS agreements with AstraZeneca, Moderna, and Johnson & Johnson respectively include investments in manufacturing capabilities.
June 1: HHS announced a task order with Emergent BioSolutions to advance domestic manufacturing capabilities and capacity for a potential COVID-19 vaccine as well as therapeutics, worth approximately $628 million.
May 12: DoD and HHS announced a $138 million contract with ApiJect for more than 100 million prefilled syringes for distribution across the United States by year-end 2020, as well as the development of manufacturing capacity for the ultimate production goal of over 500 million prefilled syringes in 2021.
June 9: HHS and DoD announced a joint effort to increase domestic manufacturing capacity for vials that may be needed for vaccines and treatments:
$204 million to Corning to expand the domestic manufacturing capacity to produce an additional 164 million Valor Glass vials each year if needed.
$143 million to SiO2 Materials Science to ramp up capacity to produce the company’s glass-coated plastic container, which can be used for drugs and vaccines.
COVPN
On July 8, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), has established a new clinical trials network the COVID-19 Prevention Trials Network (COVPN). COVPN combines four clinical trial networks funded by NIAID: the HIV Vaccine Trials Network (HVTN), based in Seattle; the HIV Prevention Trials Network (HPTN), based in Durham, N.C.; the Infectious Diseases Clinical Research Consortium (IDCRC), based in Atlanta; and the AIDS Clinical Trials Group, based in Los Angeles.
COVPN website describes their mission to conduct Phase 3 vaccine and monoclonal antibody efficacy studies for the prevention of COVID-19. They promise to publish more information on the progress of the COVID-19 trials, once it becomes available.
Vaccines prevent diseases that can be dangerous, or even deadly. Vaccines greatly reduce the risk of infection by working with the body’s natural defenses to safely develop immunity to disease.
Immune System
When germs or pathogens infect the body, the immune system uses several mechanisms to fight infections. First line of defense is the innate immune system which we inherit at birth. It consists of leukocytes – white blood cells, and the compliment system. Innate immune system is fast and non-specific to pathogens. The Natural Killer cells destroy our own cells infected by pathogens of any type. The compliment system produces proteins and enzymes, which can recognize the specific antigen (a toxin which triggers immune response) present on the surface of the pathogen and signal to the adaptive or acquired immune system.
The cells of the acquired immune system are lymphocytes (B cells and T cells). The Killer T cells directly kill pathogens. The B cells create antibodies – Y-shaped proteins – which recognize specific pathogen, connect to it and signal to other cells to come and destroy it. B cells preserve immunological memory of the specific antigen and in case of another infection produce appropriate antibodies right away. Adaptive immune system is specific rather than inherited, and as such is more potent than the innate immune system.
How Vaccines Work
Vaccines develop immunity by imitating an infection and causing the immune system to produce T cells and antibodies. Sometimes, after getting a vaccine, the patient can develop minor symptoms, such as fever. It takes some time for the body to develop T cells and B cells after vaccination to provide protection.
Types of Vaccines for COVID-19
Following description of the vaccine types is based on the information from the Milken Institute COVID-19 vaccine tracker.
Inactivated Virus: Made from the disease-causing virus that has been killed with heat or chemicals, an inactivated virus vaccine will not make you sick. It can be used in people that may not be able to use a live attenuated virus vaccine (e.g., immunocompromised). Inactivated virus vaccines may not provide as strong of an immune response as live attenuated virus vaccines, so a series of inoculations may be needed for a strong immune response. Still, this vaccine type is used widely, a safer choice for many people. Well known examples of inactivated virus vaccines include polio and influenza.
Live Attenuated Virus: In contrast to inactivated virus vaccines, these vaccines consist of whole live viruses, weakened to reduce virulence but eliciting a strong immune response. Examples of live attenuated virus vaccines include those measles, mumps, and tuberculosis.
Protein Subunit: Rather than introducing whole viruses to an immune system, a fragment of the virus is used to trigger an immune response and stimulate immunity. Examples of protein subunit vaccines include hepatitis B and shingles.
DNA-based: DNA-based vaccines are made by inserting a genetically engineered blueprint of viral gene(s) into small DNA molecules called plasmids. After plasmids are injected, cells use the DNA instructions to build viral proteins, which the immune system recognizes as foreign. This triggers the immune response and develops resistance to the disease. DNA-based vaccines can potentially be developed more rapidly than other vaccine types, but no DNA vaccines have been approved for human use to date.
RNA-based: Similar in principle to DNA vaccines, this experimental vaccine type produces immunity through introduction of RNA genetic material. RNA vaccines also have the potential to be developed more rapidly than other vaccine types, but no RNA vaccines have been approved for human use to date.
Replicating Viral Vector: This vaccine type involves inserting a gene for a viral protein into a different virus, one that will not cause illness but can replicate. The viral vector replication also produces copies of the target viral protein, triggering an immune response to that protein. Examples of replicating viral vector vaccines include Ebola and dengue.
Non-Replicating Viral Vector: Somewhat similarly to replicating viral vector vaccines, the target viral gene is added to a different, non-replicating, virus and then delivered to the vaccine recipient. No vaccine of this kind has been approved to date.
Virus-Like Particle: Virus-like particle (VLP) vaccines closely resemble the virus, but are not infectious because they contain no genetic material. VLP vaccines provide a safer alternative to an attenuated virus vaccines, and one example of this vaccine type is HPV.
Other: Ranging from a gene-encoded antibody vaccine to a self-assembling vaccine, some of the innovative forms of vaccines under development do not fall readily into one of the established categories.
Highly safe and effective vaccines plus population readily accepting vaccination are keys to stopping COVID-19 pandemic. Vaccine hesitancy – the reluctance or refusal to vaccinate despite the availability of vaccines – the World Health Organization (WHO) lists by among the ten greatest threats to global health.
Public confidence in vaccination can be established if there is full transparency around the data on development, testing and roll-out of vaccines targeting COVID-19. In the US, the Chairman of the Subcommittee on Economic and Consumer Policy issued a statement on FDA process for review and license or authorize any vaccine candidates for the novel coronavirus:
To instill public confidence in an eventual vaccine, our expert panelists testified to the importance of a clear and transparent FDA review process, starting with large 30,000 person clinical trials and involving FDA’s consultation with an advisory committee made up of independent experts
In the UK, an open letter “The 10-point vaccine transparency approach” was sent to the Secretary of State by a coalition of health organizations, pointing out key areas for vaccine transparency:
Full disclosure of all raw data from safety studies of commercial COVID-19 vaccines
Transparency in relation to safety and efficacy studies
Transparency over the type of platform used for commercial vaccines
Conduct and transparency of studies to elucidate any risks associated with adjuvants as distinct from antigens
Transparency in relation to a vaccine composition
Full disclosure of cases and potential cases of vaccine injury
The Government must clarify eligibility and criteria for no-fault vaccine injury payments for COVID-19 vaccines
The Government must clarify indemnity offered to vaccine manufacturers
The public must be informed of the extent of naturally acquired immunity prior to the public release of COVID-19 vaccines
Parliament must be engaged to ensure due democratic process if the Government is planning to consider making COVID-19 vaccines mandatory
Tracking Organizations
COVID-19 pandemic has created unprecedented public/private partnerships in developing treatments and vaccines. Government, private and non-profit organizations created databases, trial trackers and other resources to establish transparency and provide access to the trial materials. Here are some of those resources which differ in the range of information, formats and frequency of updates.
Milken Institute FasterCures Center COVID-19 Treatment and Vaccine Tracker contains publicly-available information from validated sources. A visualized presentation for the vaccine tracker lists leading candidates ranked by the phase of development. Vaccines are grouped by type:
inactivated virus
live attenuated virus
protein subunit
DNA-based
RNA-based
replicating viral vector
non-replicating viral vector
virus-like particle
The New York Times Coronavirus Vaccine Tracker provides a total number of the vaccines and a list which can be filtered by the stage of development: Preclinical, Phase I, Phase II, Phase III, Approved. List of All vaccines is organized by type: Genetic Vaccines, Viral Vector Vaccines, Protein-Based Vaccines, Whole-Virus Vaccines, Repurposed Vaccines.
Regulatory Affairs Professionals Society (RAPS)COVID-19 vaccine tracker lists COVID-19 vaccine candidates currently in Phase 1-3 trials, as well as major candidates in pre-clinical stages of development and research.
WHO Draft Landscape of COVID-19 candidate vaccines offers for download a seven pages PDF file. Candidate Vaccines are listed in two tables: in clinical evaluation and preclinical evaluation. Information on a platform, vaccine type, developer, stage of clinical evaluation is provided for each candidate vaccine.
The Global Health NetworkCoronavirus Ongoing Trials has 13 entries which list databases, trial trackers, publications trackers created by different organizations.
