Candidate: BNT162b2 (Conditionally authorized in Europe as COMIRNATY® )
Type: Nucleoside modified mRNA (modRNA) candidate encoding an optimized SARS-CoV-2 full-length spike protein antigen. BNT162b2 is the lead candidate of the Pfizer/BioNTech BNT162 program, which includes another modRNA candidate that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen antigen; a uridine containing mRNA (uRNA) candidate; and a candidate using self-amplifying mRNA (saRNA). The other candidates are known as BNT162a1, BNT162b1, and BNT162c2.
Each mRNA format is combined with a lipid nanoparticle (LNP) formulation. The larger spike sequence is included in two of the candidates, while the smaller optimized receptor binding domain (RBD) from the spike protein is included in the other two candidates.
2021 Status: Pfizer and BioNTech said February 25 they are studying the safety and immunogenicity of a booster third dose of BNT162b2, reasoning that it can better protect against variants of SARS-CoV-2. The study will evaluate up to 144 U.S. participants from the companies’ Phase I study of the vaccine in two age cohorts, 18-55 and 65-85 years of age. Participants will be offered the opportunity to receive a 30 µg booster of the current vaccine 6 to 12 months after receiving their initial two-dose regimen.
“We believe that the third dose will raise the antibody response 10- to 20- fold,” CEO Albert Bourla, DVM, PhD, told “NBC Nightly News” anchor Lester Holt in an interview.
Separately, Pfizer and BioNTech said they were in ongoing discussions with regulatory authorities, including the FDA and European Medicines Agency, about conducting a registration-enabling clinical study to evaluate a variant-specific vaccine having a modified mRNA sequence. This study would use a new construct of the Pfizer-BioNTech vaccine based on the South African B.1.351 variant. “This could position the companies to update the current vaccine quickly if the need arises to protect against COVID-19 from circulating strains,” according to Pfizer and BioNTech.
Bourla, speaking after a February 19 visit by President Joe Biden to Pfizer’s Portage, MI, manufacturing facility, said his company expects to “more than double” the 5 million doses of BNT162b2 it will supply the U.S. in the next few weeks, among 300 million doses committed to the nation by the end of July.
“We have improved our processes to double the batch size and increase yield and we have deployed more efficient lab test methods to reduce release times,” Bourla said. Those measures allowed the company to reduce the time it takes to make the vaccine from 110 days to 60 days, he added.
Also on February 19, Pfizer and BioNTech said they submitted new data to the FDA showing the stability of their COVID-19 vaccine when stored at -25°C to -15°C (-13°F to 5°F), temperatures commonly found in pharmaceutical freezers and refrigerators. The data is intended to support a proposed update to the Emergency Use Authorization (EUA) Prescribing Information that would allow for vaccine vials to be stored at these temperatures for a total of two weeks as an alternative or complement to storage in an ultra-low temperature freezer. Labels for the Pfizer-BioNTech COVID-19 vaccine, including the EUA label in the U.S., now state that the vaccine must be stored in an ultra-cold freezer at temperatures between -80ºC and -60ºC (-112ºF to ‑76ºF) for up to 6 months.
The vaccines are shipped in a specially-designed thermal container that can be used as temporary storage for a total of up to 30 days by refilling with dry ice every five days. Before mixing with a saline diluent, the vaccine may also be refrigerated for up to five days at standard refrigerator temperature, between 2⁰C and 8⁰C (36⁰F and 46⁰F). If approved, the option to store at -25°C to -15°C (-13°F to 5°F) for two weeks would be in addition to this five-day option to store at standard refrigerator temperature. The vaccine is administered at room temperature by medical staff.
A day earlier, researchers at Sheba Medical Center in Israel published a study in The Lancet showing an 85% reduction in the rate of COVID-19 15–28 days after the first dose among 7,214 hospital staffers vaccinated in January, and 95% effective after the two doses, 21 days apart, called for in the label. The overall rate reduction of SARS-CoV-2 infections was 75% in patients 15–28 days after the first dose.
Pfizer and BioNTech said February 18 that the first participants were dosed in a global Phase II/III trial (NCT04754594) designed to assess BNT162b2 in preventing COVID-19 in healthy pregnant women 18 years of age and older. The trial is designed as a randomized, placebo-controlled, observer-blind study in approximately 4,000 healthy pregnant women 18 years of age or older vaccinated during 24 to 34 weeks of gestation.
The study is designed to evaluate the safety, tolerability, and immunogenicity of two doses of BNT162b2 or placebo administered 21 days apart. Each woman will participate in the study for approximately 7 to 10 months, depending on whether she was randomized to receive the vaccine or placebo. The study will assess safety in infants of vaccinated pregnant women and the transfer of potentially protective antibody to their infants. Infants will be monitored through approximately six months of age. According to the study protocol, maternal trial participants will be unblinded after their babies are born, and those in the placebo group will receive the vaccine.
Pfizer and BioNTech also disclosed plans for additional studies in children ages 5-11 over the next couple of months, and in children younger than 5 later in 2021. Safety and efficacy in subjects 12 to 15 years of age are being evaluated in the global Phase III study (NCT04368728), with data set to be submitted to regulators in the second quarter. Further studies of the vaccine are planned in people with compromised immune systems.
Researchers from Pfizer, BioNTech, and the University of Texas Medical Branch published a letter February 17 in The New England Journal of Medicine reporting results from an in vitro study assessing the capability of sera from individuals immunized with BNT162b2 to neutralize SARS-CoV-2 with the South African variant spike protein.
The researchers acknowledged a two-thirds weakening in neutralization of virus that included the full set of spike glycoprotein mutations found in the South African variant (B.1.351 lineage), one of three variations of SARS-CoV-2 studied; the other two had subsets of the mutations. The viruses were tested against a panel of sera from 20 participants in the companies’ Phase III trial who had been immunized with BNT162b2.
“It is unclear what effect a reduction in neutralization by approximately two thirds would have on BNT162b2-elicited protection from Covid-19 caused by the B.1.351 lineage of SARS-CoV-2,” the researchers wrote, since the onset of protection after one dose of BNT162b2 precedes the development of high neutralizing titers, and BNT162b2 immunization also elicits CD8+ T-cell responses.
In a statement, Pfizer and BioNTech stressed that all the sera neutralized all the viruses tested, and that there was no clinical evidence to date that the South African variant virus escaped BNT162b2-elicited protection from COVID-19 in vaccinated people.
President Joe Biden said February 11 that the U.S. government agreed to purchase an additional 100 million doses of BNT162b2, bringing to 300 million the number of doses of the vaccine it has committed to purchasing. WWashington will also buy another 100 million doses of the Moderna COVID-19 Vaccine, Biden said during a speech at the NIH headquarters in Bethesda, MD.
Researchers from Pfizer and the University of Texas Medical Branch (UTMB) published a study February 8 in Nature Medicine containing data from in vitro studies showing that sera from individuals vaccinated with the PfizerBioNTech COVID-19 vaccine neutralize SARS-CoV-2 with key mutations present in the U.K. and South African variants. The data was originally posted January 27 on the bioRxiv server.
A subject expert committee of the Drugs Controller General of India rejected Pfizer’s application for emergency use authorization of BNT162b2, absent a plan by the company to generate safety and immunogenicity data among an Indian population from local clinical trials. The committee also said it was looking into global reports of adverse effects attributed to the vaccine, including cases of palsy and anaphylaxis. Pfizer responded by withdrawing its application and said it would submit additional data as it becomes available in the near future.
Also on February 5, Merck KGaA, Darmstadt, Germany, said it agreed with BioNTech to expand a strategic partnership by “significantly” accelerating the supply of lipids and increasing the amount of lipids delivered to BioNTech towards the end of 2021. The lipids will be used for the production of BNT162b2.
Novartis said January 29 that it signed an initial agreement to manufacture BNT162b2 at its aseptic manufacturing facilities in Stein, Switzerland. Novartis said it agreed to take bulk mRNA active ingredient from BioNTech and fill itinto vials under aseptic conditions for shipment to BioNTech for their distribution to healthcare customers worldwide. Subject to a final agreement, Novartis said it planned to begin production in the second quarter.
Novartis added that its manufacturing team was in “advanced” talks with additional companies toward assuming additional manufacturing activities such as mRNA production, therapeutic protein production, and raw material production for COVID-19 vaccines and therapeutics. Specifics will be disclosed once those talks are concluded, according to the company.
Pfizer and BioNTech said January 22 that they reached an advance purchase agreement with COVAX for up to 40 million doses of BNT162b2. COVAX is a global initiative coordinated by the Global Alliance for Vaccines and Immunization (GAVI), the Coalition for Epidemic Preparedness Innovations (CEPI) and the World Health Organization (WHO), to ensure equitable access to COVID-19 vaccines for all countries, regardless of income levels.
The 92 low- and lower-middle-income countries within COVAX’s Advanced Market Commitment (AMC) financial mechanism—designed to help them secure access to COVID-19 vaccines at the same time as higher-income countries—will receive the vaccine “at a not-for-profit price,” the companies said. Doses will be delivered throughout 2021.
Also on January 22, The New York Times reported that Pfizer plans to count the sixth dose that pharmacists discovered in vials said to contain only five toward its previous commitment of 200 million doses of BNT162b2 by the end of July—thus providing fewer vials than once expected for the U.S. Pfizer persuaded the FDA on January 6 to revise the vaccine’s emergency use authorization to formally acknowledge that the vials contain six doses, not five—as has been done by the World Health Organization and European Medicines Agency.
The sixth dose requires extraction from specialized low dead volume syringes whose supply is in question. White House press secretary Jen Psaki said January 21 that the Biden administration may accelerate production of the specialized syringes to increase their supply via the Defense Production Act.
On January 19, researchers from BioNTech, Pfizer, and Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz—BioNTech CEO Ugur Sahin served as corresponding author—posted a preprint on the bioRxiv server showing that the immune sera of 16 participants in the companies’ Phase III trial of BNT162b2 (NCT04368728) had equivalent neutralizing titers to both the Wuhan reference strain of SARS-CoV-2 and the U.K. variant strain of SARS-CoV-2, known as B.1.1.7 lineage or VOC 202012/01.
“These data, together with the combined immunity involving humoral and cellular effectors induced by this vaccine, make it unlikely that the B.1.1.7 lineage will escape BNT162b2-mediated protection,” the researchers concluded.
Israel’s Ministry of Health on January 17 published an agreement reached with Pfizer on January 6, through which Pfizer agreed to provide more doses of BNT162b2, “a product delivery rate to allow maintaining a vaccination rate sufficient to achieving herd immunity and enough data as soon as possible.”
In return, the ministry committed to sharing weekly data with Pfizer related to: Confirmed COVID-19 cases, hospitalizations, severe/critical cases, ventilator use, deaths, and symptomatic cases, as well as weekly numbers of cases; numbers of vaccines (total as well as by age and other demographic subgroups), and additional subgroup analyses and vaccine effectiveness analyses, as agreed upon by Pfizer and the Ministry.
Pfizer confirmed to the Associated Press on January 15 that “fewer doses will be available for European countries at the end of January and the beginning of February,” while it upgrades its factory in Puurs, Belgium to fulfill the company’s commitment, made four days earlier, to ramp up its annual production capacity of COMIRNATY to 2 billion doses a year. BioNTech said in a regulatory filing that the increased capacity followed improvements and expansions at production facilities, and capacity increases at suppliers and production partners.
A week earlier on January 8, the European Medicines Agency approved raising the number of doses drawn from each vial from five to six, a 20% increase in the number of available doses.
Also that day, researchers from Pfizer and the University of Texas Medical Branch (UTMB) posted results from an in vitro study on the preprint server bioRxiv showing that antibodies from people who have received COMIRNATY effectively neutralize SARS-CoV-2 with the N501Y mutation that is also found in two highly transmissible strains. A virus with the mutation was generated in UTMB’s laboratory. The sera of 20 participants from the Phase III trial neutralized the virus with the mutation as well as neutralized virus without the mutation.
The companies cautioned that the tested virus did not include the full set of spike mutations found on the rapidly spreading strains in the U.K. or South Africa—yet neutralization of virus with the N501Y mutation by the human sera elicited by the vaccine was consistent with preserved neutralization of a panel of 15 pseudoviruses bearing spikes with other mutations found in circulating SARS-CoV-2 strains. According to Pfizer and BioNTech, that result indicated that the key N501Y mutation does not create resistance to the Pfizer-BioNTech vaccine induced immune responses.
Pfizer and BioNTech have disclosed on the website of their Phase III trial (NCT04368728) that all participants ages 16 and older have the option to receive BNT162b2 by March 1 while continuing to be part of the clinical study. All participants 16 years and older who received the placebo have two doses of the investigational vaccine reserved for them within the study. Participants who choose the “Vaccine Transition Option” will be scheduled by their study site to be unblinded “in the coming weeks,” with participants choosing to receive the vaccine having to sign a new consent form following review with a study doctor before receiving their first dose of COMIRNATY.
2020 Status: EU orders 300M doses — Pfizer and BioNTech on December 29 said they agreed to supply an additional 100 million doses of COMIRNATY®, the companies’ recently renamed COVID-19 vaccine, to the European Union’s 27 member states in 2021 for an undisclosed price, after the EU exercised an option for the additional doses. The EU has ordered a total 300 million doses.
The expanded order came a week after the EMA’s Committee for Medicinal Products for Human Use (CHMP) on December 21 issued a positive opinion recommending the conditional marketing authorization (CMA) of BNT162b2 for active immunization to prevent COVID-19 caused by SARS-CoV-2 virus, in individuals 16 years of age and older.
CHMP advisors based their positive opinion on positive data supporting BNT162b2, including data from a Phase III clinical study published December 10 in The New England Journal of Medicine (See below). The European Commission (EC) is expected to make a final decision on the conditional marketing authorization in the near future. If the EC grants the CMA, the decision will immediately apply to all 27 EU member states. To date, the vaccine has been authorized or approved for emergency or temporary use in more than 15 countries.
The Swiss Agency for Therapeutic Products (Swissmedic) authorized BNT162b2 on December 19, a day after the vaccine received a favorable recommendation from Swissmedic’s independent advisory body, the Human Medicines Expert Committee (HMEC). BNT162b2 was approved under the name COMIRNATY™, which was trademarked by BioNTech based on an application filed June 1 with the U.S. Patent & Trademark Office.
On December 14, researchers from Pfizer and BioNTech on December 14 posted preprint results on medRxiv from a Phase I/II trial (NCT04380701) of BNT162b2 in Germany showing that the vaccine elicited a combined adaptive humoral and cellular immune response against SARS-CoV-2. All 37 participants vaccinated with BNT162b2 showed newly generated spike protein-specific CD4+ T cell responses, and almost 92% of participants demonstrated CD8+ T cell responses. Pfizer said the majority were strong T cell responses comparable to or significantly higher than memory responses of the same individuals against common viruses, such as cytomegalovirus (CMV), Epstein Barr virus (EBV) and the influenza virus.
Even at the lowest dose of 1 µg BNT162b2, Pfizer added, most vaccinated participants elicited robust expansion of CD4+ and CD8+ T cells. Expression of cytokines IFNγ and IL-2, but only low levels of IL-4 in BNT162b2-induced CD4+ T cells indicated a TH1 profile. CD8+ T cell responses were directed against multiple regions of the spike protein, and several of the multiple epitopes recognized by BNT162b2-induced CD8+ T cells were molecularly identified.
FDA AUTHORIZES EMERGENCY USE–The FDA on December 11 granted the companies an emergency use authorization (EUA) for BNT162b2 for the prevention of COVID-19 in individuals 16 years of age and older. The companies have begun distributing the two-dose vaccine, with 2.9 million doses set to be shipped the following week.
The FDA’s approval followed months of intense pressure on the agency and Hahn to act quickly on the companies’ EUA application from President Trump—pressure that he intensified on on December 11 with a tweet faulting what he contended was the agency’s overly slow response to the Pfizer and BioNTech EUA application for BNT162b2, submitted November 20.
“It is still a big slow turtle,” Trump said of the FDA, demanding of Hahn: “Get the dam[n] vaccines out NOW, Dr. Hahn @SteveFDA. Stop playing games and start saving lives!!”
The EUA made the United States the fifth country to approve BNT162b2, after the U.K., Bahrain, Canada, and Saudi Arabia.
FDA Panel Recommends Approval — By a 17-4 vote with one abstention, the FDA’s Vaccine and Related Biologic Products Advisory Committee on December 10 recommended agency approval of BNT162b2, with a majority agreeing that based on the totality of scientific evidence available, the benefits of BNT162b2 outweighed its risks for use in individuals 16 years of age and older.
During a discussion period before the vote, committee members discussed a handful of adverse reactions to the vaccine in the U.K., whose drug and vaccine regulator, the Medicines and Healthcare Products Regulatory Agency (MHRA), disclosed two reports of anaphylaxis and one of a possible allergic reaction since the start of patient dosing on December 8.
Among FDA advisory committee members who voted yes was Paul A. Offit, MD, director of the Vaccine Education Center and an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia. Offit earlier noted the reports of allergic patients in the U.K., and expressed concerns that Americans with severe allergies would shy away from taking BNT162b2 absent additional study by the companies about the vaccine’s effects in such people: “This issue is not going to die until we have better data.”
Responding to Offit, Marion Gruber, PhD, Director of the FDA’s Office of Vaccines Research and Review, noted that the agency had included a warning for people with a history of allergy to any component of BNT162b2 in the vaccine’s prescribing information.
Earlier on December 10, researchers from Pfizer, BioNTech and their clinical partners confirmed the vaccine’s 95% efficacy rate in “Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine,” a study published in The New England Journal of Medicine. According to that study, the 95% credible interval for vaccine efficacy (VE) was 90.3% to 97.6%, indicating that the true VE was at least 90.3% with a 97.6% probability given the available data.
Among 10 cases of severe COVID-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The one severe COVID-19 participant was thus classified after a drop in oxygen levels, William Gruber, Pfizer senior vice president for vaccine research, said at the advisory committee hearing.
FDA staff scientists on December 8 issued a Briefing Document in advance of the Vaccines and Related Biological Products Advisory Committee meeting of December 10 that confirmed the positive Phase III data announced days earlier by Pfizer and BioNTech. The data showed the efficacy of the vaccine to be 95.0%, with eight COVID-19 cases in the BNT162b2 group compared to 162 COVID-19 cases in the placebo group. The 95% credible interval for vaccine erfficacy (VE) was 90.3% to 97.6%, indicating that the true VE is at least 90.3% with a 97.5% probability given the available data, the FDA scientists reported.
“The final efficacy results show that BNT162b2 at 30 µg provided protection against COVID-19 in participants who had no evidence of prior infection with SARS-CoV-2, including across demographic subgroups, with severe cases observed predominantly in the placebo group,” the researchers wrote.
There were no clinically meaningful differences in demographic characteristics by subgroups, they added. Overall, about 42% of the Phase II/III trial’s evaluable efficacy population had racially and ethnically diverse backgrounds—including 26.2% of participants who identified as Hispanic or Latinx; 9.8% as black or African-American; 4.4% as Asian; 0.7 as American Indian or Alaska Native; and 0.3% as Native Hawaiian or Other Pacific Islander. Another 2.6% identified as multiracial.
Just under half were female (49.4%), while 21.4% of participants were >65 years of age. Geographically, 76.7% of participants were from the US, 15.3% from Argentina, 6.1% from Brazil, and 2% from South Africa.
Bahrain’s National Health Regulatory Authority on December 4 granted emergency use authorization for BNT162b2—the second COVID-19 treatment to gain an approval from the kingdom. The Authority said the vaccine will be made available to groups at greater risk of contracting complications from COVID-19, including senior citizens, people with chronic diseases, and other groups identified by the heath ministry as vulnerable.
UK grants temporary authorization — Pfizer and BioNTech received temporary authorization November 30 from the U.K.’s Medicines & Healthcare Products Regulatory Agency (MHRA) for emergency use of BNT162b2—giving the companies their first authorization for a vaccine designed to protect against the virus. The first doses are being shipped for arrival in the U.K. in coming days, with a reported 800,000 doses expected. Those first doses will be distributed to senior citizens in nursing homes, staffers of those homes, and healthcare workers, the BBC reported.
A day earlier, Pfizer and BioNTech applied in Europe for conditional marketing authorisation (CMA) for BNT162b2, with an advisory committee hearing set for December 11.
Companies apply for FDA Emergency Use Authorization — Pfizer and BioNTech applied November 20 for emergency use authorization (EUA) of BNT162b2, with the first doses expected to reach people at high risk of the virus as soon as December 2020. The companies said they supported their EUA application in part with final efficacy data they announced earlier that week, as well as with positive safety data.
The companies will combine solicited safety data from a randomized subset of approximately 8,000 participants ≥18 years of age, with unsolicited safety data from approximately 38,000 trial participants who were followed for a median of two months following the second dose of the two-dose vaccine candidate—the time period for safety data specified in FDA EUA guidance for emergency use applications. The EUA submission also included solicited safety data on approximately 100 children 12–15 years of age, the companies added.
Pfizer and BioNTech on November 18 released data from a final efficacy analysis in their nearly 44,000-patient Phase III trial of BNT162b2 showing the COVID-19 vaccine candidate to have achieved 95% effectiveness, thus meeting the study’s first primary objective, in participants without prior SARS-CoV-2 infection.
Just 8 of 170 COVID-19 cases that arose during the trial were contracted by participants randomized to BNT162b2 while the other 162 cases were seen in the group of patients randomized to placebo, Pfizer and BioNTech said. That 95% efficacy rate is based on nearly twice as many COVID-19 cases as the 94 cases reported in data from a first efficacy analysis that showed the vaccine to be more than 90% effective, released a week earlier.
Pfizer and BioNTech on November 11 said they reached agreement with the European Commission to supply 200 million doses of BNT162b2 to European Union (EU) Member States, with an option for the European Commission to request an additional 100 million doses. The value of the agreement was not disclosed.
Deliveries are expected to begin by the end of 2020, subject to clinical success and regulatory authorization. Vaccine doses for Europe will be produced at BioNTech’s German manufacturing sites, as well as at Pfizer’s manufacturing site in Puurs-Sint-Amands, Belgium. Upon European approval, the European Commission will lead a process of allocating doses of BNT162b2 among the EU Member States which have elected to receive the vaccine.
Two days earlier, Pfizer and BioNTech announced that BNT162b2 aced its Phase III trial according to early data showing the vaccine to be more than 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection, in the study’s first interim efficacy analysis. The external, independent Data Monitoring Committee (DMC) of the Phase III trial (NCT04368728) carried out the analysis, which included assessing 94 confirmed cases of COVID-19 among the trial’s 43,538 participants to date—of which 38,955 had already received their second dose of BNT162b2.
Pfizer and BioNTech now estimate that a median of two months of safety data following the second and final dose of the vaccine candidate—the amount of safety data specified by the FDA in its guidance for potential EUAs—will be available by the third week of November. The companies said they plan to file for an EUA for their vaccine “soon after.”
“Today is a great day for science and humanity,” declared Albert Bourla, DVM, PhD, Pfizer Chairman and CEO, in a statement.
BioNTech and Germany are developing a plan under which the country would be one of the first in the West to begin immunizing people with a COVID-19 vaccine, The Wall Street Journal reported October 29 based on unnamed sources. Under the plan, doses of the vaccine being stored at a secret transport hub in Germany would be shipped to more than 60 regional vaccination centers within hours of approval. Initial recipients would include health-care workers, the elderly, clinically vulnerable people, law-enforcement officials and people living in crowded conditions.
Germany’s vaccination plan could be rolled out before the end of 2020 depending on results of late-stage clinical trials, the WSJ reported.
Pfizer Chairman and CEO Albert Bourla, DVM, PhD, wrote October 16 in an open letter that should BNT162b2, the current lead candidate of the BNT162 program, prove safe and effective, Pfizer and BioNTech will apply for Emergency Use Authorization (EUA) of their vaccine. He noted the FDA requirement that EUA applications be supported by at least two months of safety data on half of the trial participants following the final dose of the vaccine.
“Assuming positive data, Pfizer will apply for Emergency Authorization Use in the U.S. soon after the safety milestone is achieved in the third week of November, Bourla wrote.
Pfizer and BioNTech said October 9 that they initiated a rolling submission to Health Canada for BNT162b2, the current lead candidate of the BNT162 program. The rolling submission has been accepted under the Minister of Health’s Interim Order allowing companies to submit safety and efficacy data and information as they become available.
Three days earlier, the companies launched a rolling submission to the European Medicines Agency (EMA) for BNT162b2. The EMA’s decision to start a rolling review followed encouraging preliminary results from preclinical and early clinical studies in adults, which suggested that BNT162b2 triggered the production of neutralizing antibodies and TH-1 dominant CD4+ and CD8+ T cells that target SARS-CoV-2.
As part of the European rolling review, the EMA’s Committee for Medicinal Products for Human Use (CHMP) has begun evaluating data generated in pre-clinical trials. The formal MAA submission could be finalized following the rolling review process, pending demonstration of vaccine efficacy and safety and confirmation from the EMA that the submitted data are adequate, Pfizer and BioNTech said.
BNT162b2 is under study in a global Phase III trial (NCT04368728) now ongoing at more than 120 clinical sites worldwide. To date, the trial has enrolled approximately 37,000 participants with more than 28,000 having received their second vaccination.
BioNTech said September 17 it agreed to acquire Novartis’ GMP certified manufacturing facility in Marburg, Germany for an undisclosed price, in a deal expected to close during the fourth quarter. The Marburg site will expand BioNTech’s COVID-19 vaccine production capacity by up to 750 million doses per year, or over 60 million doses per month, once fully operational.
The Marburg facility is expected to start the production of mRNA and the LNP formulation for a COVID-19 vaccine in the first half of 2021, pending regulatory authorization or approval. In the first half of 2021, BioNTech said, it plans to produce up to 250 million doses of BNT162b2 at Marburg, which employs approximately 300 people.
BioNTech added that it intends to use the Marburg facility to contribute to the production of the COVID-19 vaccine for global supply—including to China, where it has partnered with Fosun Pharma.
Two days earlier, BioNTech said it will receive a €375 million ($444 million) grant from the German Federal Ministry of Education and Research (BMBF) to support accelerated development of the BNT162 vaccine program with partners Pfizer and Fosun Pharma. BMBF plans to fund a total €750 million ($888 million) to developers of three COVID-19 vaccine programs under an initiative designed to expand vaccine development and manufacturing capabilities in Germany, as well as expand the number of participants in late-stage clinical trials.
A week earlier on September 7, BioNTech received regulatory approval from the Paul-Ehrlich-Institut to expand into Germany its nearly global Phase II/III clinical trial evaluating BNT162b2, with the goal of supporting an approval for the vaccine in Europe.
The Phase II/III trial is designed to evaluate two BNT162b2 in up to 30,000 participants aged 18–85 years, at approximately 120 sites globally—including in regions with significant expected SARS-CoV-2 transmission. As of September 7, the trial had enrolled more than 25,000 participants, BioNTech and Pfizer said, with the study’s ultimate enrollment estimated at 29,481.
Participants will be randomized 1:1, vaccine candidate to placebo in the observer-blinded study, whose primary endpoints will be prevention of COVID-19 in those who have not been infected by SARS-CoV-2 prior to immunization, and prevention of COVID-19 regardless of whether participants have previously been infected by SARS-CoV-2. The trial’s secondary endpoints include prevention of severe COVID-19 in both groups.
The study will also explore prevention of infection by SARS-CoV-2. The primary efficacy analysis will be based on the number of participants with symptomatic COVID-19 disease, Pfizer and BioNTech added.
Assuming clinical success, Pfizer and BioNTech said, they are on track to seek regulatory review for BNT162b2 as soon as October 2020. Upon regulatory authorization or approval, the companies plan to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses by the end of 2021
“About 19% or so” of the 11,000 participants recruited by Pfizer and BioNTech as of August 21 for the Phase II/III trial were Black or Latinx, Bill Gruber, MD, FAAP, FIDSA, Senior Vice President of Pfizer Vaccine Clinical Research and Development, told Reuters, adding: “We’re trying to push even higher than that.”
The companies are in talks with the FDA on a safety plan enabling them to test the vaccine in children. Pfizer and BioNTech expect to have enough data by October for either an emergency use authorization or a full NDA submission, Gruber added.
Investigators from Pfizer, BioNTech, and their research partners on August 20 posted a preprint in medRxiv detailing the Phase I data that led to their switch of lead candidates in their BNT162 vaccine program from BNT162b1 to BNT162b2, announced in July.
According to the data, both BNT162b1 and BNT162b2 elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers (GMTs), comparable to or higher than the GMT of a panel of SARS-CoV-2 convalescent sera. However, BNT162b2 led to milder systemic events that BNT162b1, especially in older adults: Only 17% of 18–55 year olds and 8% of 65–85 year olds reported fever (≥38.0–38.9°C) after Dose 2 of 30 µg BNT162b2, compared with 75% of 18–55 years old and 33% of 65-85 year olds reporting fever after Dose 2 of 30 µg BNT162b1.
The data came from the Phase I portion of a U.S. Phase I/II trial (NCT04368728; EU Clinical Trials Registry EudraCT number 2020-001038-36), a randomized, placebo-controlled, observer-blinded study designed to assess the safety, tolerability, and immunogenicity of escalating dose levels of the two vaccine candidates. Between May 4 and June 22, 195 healthy males and nonpregnant females were randomized to 13 groups of 15 participants, of which 12 received vaccine and 3 placebo per group. Groups of participants ages 18–55 and 65–85 received two doses of 10-μg, 20-μg, or 30-μg BNT162b1 or BNT162b2, 21 days apart. Another group ages 18–55 received one dose of 100 µg BNT162b1 or placebo.
Pfizer Canada and BioNTech on August 5 said they agreed to supply their BNT162 vaccine candidate to the Government of Canada. The companies did not disclose financial details but did say they were based on the timing of delivery and the volume of doses. Deliveries of the vaccine candidate are planned for over the course of 2021, at Canadian government request.
On July 31, Pfizer and BioNTech said they will supply 120 million doses of a BNT162 candidate in Japan beginning in 2021, subject to clinical success and regulatory approval, under an agreement signed with Japan’s Ministry of Health, Labour and Welfare (MHLW). While financial details were not disclosed. The companies said terms were based on the timing of delivery and the volume of doses.
“We are proud to help support Japan in its steadfast determination to bring the world together at the 2020 Tokyo Olympics, in a celebration of solidarity, friendship and the power of sport as a global force for good,” Bourla said. The Tokyo Olympics were postponed due to COVID-19, but has been rescheduled for July 23-August 8, 2021.
Four days earlier, Pfizer and BioNTech said they had advanced the four-candidate BNT162 program into an up-to-30,000 patient, nearly global Phase II/III trial—after switching their lead vaccine candidate from one nucleoside modified mRNA (modRNA) candidate to the other, citing stronger clinical data.
The companies opted to advance BNT162b2, saying that preliminary Phase I/II data from nearly 120 patients showed a more favorable overall tolerability profile than BNT162b1, with no serious adverse events and generally mild to moderate and transient systemic events such as fever, fatigue, and chills.
Two other reasons cited by Pfizer and BioNTech: Participants who were vaccinated with BNT162b2 showed a favorable breadth of epitopes recognized in T-cell responses specific to the SARS-CoV-2 antigen, compared to BNT162b1. Also, BNT162b2 elicited T-cell responses against the receptor-binding domain (RBD) and against the remainder of the spike glycoprotein that is not contained in BNT162b1. BNT162b2 showed concurrent induction of high magnitude CD4+ and CD8+ T-cell responses.
“The companies believe that immune recognition of more spike T-cell epitopes may have the potential to generate more consistent responses across diverse populations and in older adults,” Pfizer and BioNTech stated.
The companies also said they continue to collect data from the Phase I/II trials for all four vaccine candidates and expect to submit data on BNT162b2 for peer review and potential publication in the near future: “In keeping with their commitment to transparency, the companies intend to also post the manuscript on a preprint server at that time.”
Five days earlier, the companies said that the U.S. Department of Health and Human Services (HHS) and Department of Defense (DoD) ordered an initial 100 million doses of BNT162 for $1.95 billion, with the option to purchase 500 million additional doses. The companies agreed to offer BNT162 for free under an agreement signed as part of Operation Warp Speed, through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021.
The companies did not announce the price Washington would pay for the additional 500 million doses should they be ordered—but did say the agreement is subject to Pfizer successfully manufacturing and obtaining approval or emergency use authorization for the vaccine. Pfizer and BioNTech said they expect to be ready to seek emergency use authorization or some form of regulatory approval as early as October.
Pfizer and BioNTech said they expect to manufacture globally up to 100 million doses by the end of 2020, and potentially more than 1.3 billion doses by the end of 2021, subject to final dose selection from their clinical trials.
Two days earlier, Pfizer and BioNTech published initial data from an ongoing German Phase I/II, open-label, non-randomized, non-placebo-controlled, dose-escalation trial of then-lead candidate BNT162b1, (EU Clinical Trials Registry EudraCT number 2020-001038-36). The preliminary data—from a preprint study published in medRxiv—showed BNT162b1 to have elicited high, dose level-dependent SARS-CoV-2-neutralizing titers and receptor binding domain (RBD)-binding immunoglobulin G (IgG) concentrations after the second dose.
At Day 43, SARS-CoV-2 neutralizing geometric mean titers were in the range of 0.7-fold (1 µg) to 3.2-fold (50 µg) compared to that of a panel of SARS-CoV-2 infection convalescent human sera. Furthermore, sera of vaccinated subjects displayed broadly neutralizing activity in pseudovirus neutralization assays across a panel of 16 SARS-CoV-2 RBD variants represented in publicly available SARS-CoV-2 sequences and against the newly dominant D614G strain. The initial German trial results also showed for the first time a concurrent induction of high level CD4+ and CD8+ T cell responses against the SARS-CoV-2 RBD for BNT162b1—thus indicating a strong potential for cell mediated anti-viral activity, according to BioNTech and Pfizer.
“The preliminary data indicate that our mRNA-based vaccine was able to stimulate antibody as well as T-cell responses at remarkably low dose levels. We believe both may play an important role in achieving effective clearance of a pathogen such as SARS-CoV-2,” Özlem Türeci, MD, CMO and Co-founder of BioNTech, said in a statement.
BioNTech and Pfizer also announced July 20 that they committed to supply the U.K. with 30 million doses of their BNT162, to be delivered this year and next. Financial terms were not disclosed. The companies plan to seek regulatory review as early as October 2020, manufacture globally up to 100 million doses by the end of 2020, and more than 1.3 billion doses by the end of 2021.
On July 14, Fosun Pharma said its subsidiary Shanghai Fosun Pharmaceutical Industrial Development Co., Ltd. received acceptance of its clinical trial application for BNT162b1 by China’s National Medical Products Administration. A day earlier, Pfizer and BioNTech received the FDA’s Fast Track designation for BNT162b1 and BNT162b2, which are the two most advanced vaccine candidates in the BNT162 program. Both are under study in ongoing Phase I/II clinical trials in the U.S. and Germany. The designation was granted based on preliminary data from those studies, as well as animal immunogenicity studies.
Bourla told Time magazine on July 7 that he expects FDA approval for a vaccine from the BNT162 program this fall: “We should be able in the September time frame to have enough data to say if the vaccine works or not. And to submit that to the FDA. So for a potential approval in October, if we are lucky. It’s feasible.”
Pfizer and BioNTech said July 1 BNT162b1 showed encouraging immunogenicity and a favorable safety profile in preliminary data from the U.S. Phase I/II trial published in a preprint study.
“These clinical findings for the BNT162b1 RNA-based vaccine candidate are encouraging and strongly support accelerated clinical development and at-risk manufacturing to maximize the opportunity for the rapid production of a SARS-CoV-2 vaccine to prevent COVID-19 disease,” researchers concluded in the preprint study, published in medrRxiv.
Bourla told Time: “For me, it was the moment when I saw the data, plus many other data that we haven’t published yet, [that] made me say that until now I was thinking if we have a vaccine. Now I’m discussing when we’re going to have a vaccine.
BioNTech and Pfizer are evaluating four vaccine constructs of BNT162 in an mRNA-based clinical program the companies have dubbed “Project Lightspeed.”
BioNTech said June 29 it launched a $250 million private placement by new investor by Temasek and other unnamed “accredited investors.” The private placement includes an investment of approximately $139 million in ordinary shares and a $112 million investment in four-year mandatory convertible notes.
Upon closing, private placement investors will receive 2,595,996 ordinary shares in BioNTech, subject to a 180-day lock-up agreement. The four-year mandatory convertible notes will come with a coupon of 4.5% per annum and a conversion premium of 20% above the reference price. The investment is expected to close in early- to mid-August, subject to customary closing conditions, BioNTech said.
On June 3, The New York Times reported that Pfizer was among developers of five COVID-19 vaccines identified by President Donald Trump’s administration as most likely to produce a vaccine for the virus, citing unnamed “government officials.” According to the report, the five will receive additional government funding, assistance with clinical trials, and financial and logistical support for manufacturing. A formal announcement is expected in coming weeks.
Bourla predicted May 29 that “if things go well, and the stars are aligned, we will have enough evidence of safety and efficacy so that we can… have a vaccine around the end of October,” during a virtual briefing organized by International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).
Pfizer and BioNTech said they planned to scale up production for global supply, through a manufacturing program designed to allow production of millions of vaccine doses in 2020, increasing to hundreds of millions in 2021. At its own risk, Pfizer said, it will produce COVID-19 vaccines in Puurs, Belgium and sites it owns three U.S. states—with “critical” raw material manufacturing to take place in St. Louis; drug substance manufacturing in Andover; and formulation and fill in Kalamazoo, MI. BioNTech added that plans to provide further capacity for a global supply of the potential vaccine through its existing mRNA production sites in Mainz and Idar-Oberstein, Germany.
In April, CEO Bourla told analysts on the company’s quarterly conference call that his company planned to manufacture “millions of doses” of BNT162 at its own risk by the end of 2020 “to accelerate availability in the event the development program is successful and we obtain regulatory approval” for emergency use authorization. Pfizer plans to rapidly scale up its production capacity “to produce potentially hundreds of millions of doses in 2021,” he said.
BioNTech CEO Ugur Sahin told the German newspaper Welt am Sonntag April 25 that his company had ruled out being acquired after being approached by several potential acquirers he did not name: “Takeovers are out of the question for the majority shareholders and for us anyway. Our vision is to build a biopharmaceutical company that addresses the medical needs of the 21st century.”
Three days earlier, BioNTech and Pfizer said the German regulatory body Paul-Ehrlich-Institut approved the companies’ Phase I/II clinical trial for BNT162—the first clinical trial of a COVID-19 vaccine candidate to start in Germany. The companies said earlier that month they intended to launch their first clinical trials for an mRNA COVID-19 vaccine initially in the U.S. and Europe across multiple sites, with plans to advance multiple candidates.
“Given mRNA vaccine technology is in its infancy, with most data from animal studies, we like the risk diversification of this approach,” SVB Leerink Senior Research Analyst Daina M. Graybosch, PhD, and Associate Dilip Joseph wrote in an April 22 investor note. “The fact that the field has not settled on a lead mRNA technology also reminds us how early we are in development of mRNA vaccines.”
Pfizer agreed to pay BioNTech $185 million upfront—including $72 million in cash and a $113 million equity investment—and up to $563 million in payments tied to achieving milestones. Pfizer will initially fund 100% of the development costs, and BioNTech will repay Pfizer its 50% share of these costs during commercialization of the vaccine.
The companies announced their up-to-$748 million COVID-19 vaccine development partnership in March and in April revealed plans to launch a clinical trial, initially focusing on BNT162, the first treatment to emerge from BioNTech’s accelerated COVID-19-focused development program, “Project Lightspeed.” Three other candidates have since emerged.
The BioNTech-Pfizer partnership is worldwide except China, where BioNTech is partnering with Fosun Pharma to jointly develop BNT162. Fosun has agreed to make a $50 million equity investment, and pay BioNTech up to $85 million in additional upfront and milestone payments. The companies will share future gross profits from the sale of the vaccine in China.
COVID-19: 200 Candidates and Counting
To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: