Vaccine Development Status

Vaccine Nationalism

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.   

Pfizer/BioNTech

• Results of Phase III clinical trial were published on Dec. 21, 2020 in the New England Journal of Medicine, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine, F. P. Polack, et al.  [Funded by BioNTech and Pfizer; ClinicalTrials.gov number NCT04368728].
• 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].
• Moderna’s Briefing Document Addendum was published on Dec. 17, 2020. The data showed efficacy against asymptomatic infections, reflecting the impact on blocking transmission.
• 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.

Oxford/AstraZeneca

• The Lancet published on Dec. 8, 2020 an article Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa and UK, Merryn Voysey, et al. Vaccine efficacy was 62.1%  when given as two full doses and 90.0% when given as a half dose followed by a full dose.  [The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005)].
• 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.
• Pfizer/BioNTech announced that in the first interim analysis from Phase III study its vaccine candidate BTN162b2 was found to be more than 90% effective in preventing COVID-19.
• 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 announced new 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.

Screenshot from Pfizer’s video, timestamp 1:37:55

Screenshot from Pfizer’s video, timestamp 1:40:00

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.

Last Updated on April 23, 2021 by covid