Candidate: COMIRNATY® (BNT162b2)

Category: RNA, VAX

Type: Nucleoside modified mRNA (modRNA) candidate encoding an optimized SARS-CoV-2 full-length spike protein antigen. COMIRNATY 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: FDA PANEL LIMITS BOOSTER RECOMMENDATION TO 65+—The FDA’s Vaccines and Related Biological Products Advisory Committee on September 17 unanimously recommended the agency expand the Emergency Use Authorization (EUA) granted to Pfizer and BioNTech for COMIRNATY to allow for third “booster” doses in adults ages 65 and older. However, the panel voted 16-2 against recommending the booster doses be given to people ages 16 and older after a contentious hearing.

“It’s likely beneficial, in my opinion, for the elderly, and may eventually be indicated for the general population. I just don’t think we’re there yet in terms of the data,” said committee member Ofer Levy, MD, PhD, Director of the Precision Vaccines Program at Boston at Children’s Hospital, voicing a view articulated by the panel’s majority.

Another panel member, Paul Offit, MD, Director of the Vaccine Education Center at Children’s Hospital of Philadelphia, questioned if the third doses would shorten the COVID-19 pandemic as supporters of booster doses have asserted: “We all agree that if we really want to impact this pandemic, we need to vaccinate the unvaccinated.”

Canada OKs Vaccine–Health Canada has granted full approval (Notice of Compliance or NOC) for COMIRNATY® to prevent COVID-19 in individuals 12 years of age and older, Pfizer and BioNTech said September 16. The vaccine was initially authorized for use in Canada under an Interim Order Authorization on December 9, 2020.

While the vaccine will be distributed under the brand name COMIRNATY, the companies said, Canada will continue to receive vials of the vaccine labeled as Pfizer-BioNTech COVID-19 Vaccine. The formulation for Pfizer-BioNTech COVID-19 Vaccine is the same formulation as COMIRNATY and they are considered interchangeable by Health Canada.

Bourla Open Letter—Pfizer Chairman and CEO Albert Bourla, DVM, PhD, urged regulators worldwide to approve third “booster” doses for COMIRNATY in an open letter posted September 16 on the company’s website.

Bourla wrote that “breakthrough” infections in people previously vaccinated with the Pfizer/BioNTech vaccine reflected waning immunity stemming from a decline in vaccine efficacy over time, as occurs with many vaccines. Yet among cases of COVID-19 reported after July 1 by participants in the companies’ global Phase III trial (NCT04368728), those who were vaccinated later in the trial – and originally received a placebo – experienced 26% higher efficacy than those who were vaccinated earlier as part of the original group.

“These findings indicate that time from vaccination is likely a significant factor in breakthrough cases, which supports the important role that booster shots can play in helping to maintain protection against COVID-19,” Bourla asserted.

2021 Status: November Filing for Kids 5-11 Planned–At the Morgan Stanley 19th Annual Global Healthcare Conference, Pfizer CFO Frank D’Amelio said the company planned to file in November for an expanded FDA approval of COMIRNATY that would include children ages 5-11—assuming that all data concerning that age group was positive

CDC Shows Second Highest Effectiveness vs. Delta—The U.S. Centers for Disease Control and Prevention (CDC) on September 10 published a study showing greater vaccine effectiveness vs. hospitalization due to the Delta variant of SARS-CoV-2 among recipients of Moderna’s COVID-19 vaccine (95%) compared with recipients of Pfizer/BioNTech’s COMIRNATY® (80%) or Johnson & Johnson’s Janssen Single Shot COVID-19 Vaccine (60%). Among 14,636 adults hospitalized with COVID-19–like illness, lab-confirmed SARS-CoV-2 infections were identified among 18.9% (1,316 of 6,960) of unvaccinated and 3.1% (235 of 7,676) of fully vaccinated patients. The median age of hospitalized patients was 65, and patient ages ranged from 48–77 years.

Among 18,231 adults with emergency department (ED) or urgent care (UC) encounters for COVID-19–like illness, lab-confirmed SARS-CoV-2 infections were identified among 28.9% (3,145 of 10,872) of unvaccinated and 7.0% (512 of 7,359) of fully vaccinated patients. Vaccine effectiveness vs ED/UC encounters was 92% among Moderna vaccine recipients, compared with 77% for Pfizer/BioNTech and 65% for J&J.

Brazil Manufacturing Agreement—Pfizer and BioNTech said August 26 they signed a letter of intent with the Brazilian biopharma Eurofarma Laboratórios to manufacture COMIRNATY for distribution within Latin America. The value of the agreement was not disclosed. Manufacturing of finished doses will commence in 2022. At full operational capacity, the annual production is expected to exceed 100 million finished doses annually—all of which will exclusively be distributed within Latin America, the companies said.

Ugur Sahin, MD, CEO and Co-founder of BioNTech, said his company and Pfizer had delivered more than 1.3 billion doses, with plans to deliver 3 billion doses in total by the end of 2021.

Comparison vs. Natural Immunity—In a preprint posted August 25 on medRxiv, a team of Israeli researchers showed that natural immunity conferred longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2 compared to COMIRNATY.

SARS-CoV-2-naïve vaccinees had a 13.06-fold increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naïve vaccinees had a 5.96-fold increased risk for breakthrough infection and a 7.13-fold increased risk for symptomatic disease. However, patients who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant, the researchers added.

EU OKs Manufacturing Increase—The European Medicines Agency (EMA) said August 24 that its human medicines committee (CHMP) had approved an additional manufacturing site for the production of Comirnaty in Saint Rémy sur Avre, France. The site, operated by Delpharm, will enable the manufacture of approximately up to 51 million additional doses in 2021. The EMA also approved a new line at BioNTech’s manufacturing site in Marburg, Germany, that will increase its active substance manufacturing capacity by approximately 410 million doses in 2021.

FDA ISSUES FULL APPROVALPfizer and BioNTech on August 23 received the FDA’s first formal approval for a COVID-19 vaccine when the agency approved the companies’ Biologics License Application for BNT162b2, which according to the FDA will be marketed going forward as Comirnaty, its brand name in Europe. Comirnaty will be indicated for the prevention of COVID-19 disease in individuals 16 years of age and older. The vaccine will also continue to be available under emergency use authorization (EUA), for adolescents ages 12-15 years of age, as as well as for the administration of a third “booster” dose in specified immunocompromised individuals.

FDA OKs Third Dose for Some Immunocompromised People—The FDA on August 12 amended the emergency use authorizations (EUAs) for BNT162b2 and Moderna’s COVID-19 Vaccine to allow for the use of an additional dose in solid organ transplant recipients or those who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise.

FDA Reportedly Accelerating Review of Full Approval—The FDA’s Center for Biologics Evaluation will deprioritize some existing work in order to accelerate its review of the Pfizer/BioNTech BLA application for BNT162b2, STAT reported on July 30, citing an unnamed senior agency official who characterized the upcoming review as a “sprint.” CBER Director Peter Marks, MD, PhD, will “largely” oversee review of the application in place of Marion F. Gruber, PhD, Director of CBER’s Office of Vaccines Research and Review, according to the report.

Efficacy Dips from 96.2% to 83.7%–Pfizer researchers on July 28 posted a preprint study on medRxiv showing the efficacy of BNT162b2 at a robust 96.2% between one week and just under two months after receiving the second dose—then declining to 90.1% between 2 months and just under 4 months, and to 83.7% from 4 to 6 months. Of 31 cases of severe, FDA-defined COVID-19 with onset after dose 1, all but one case occurred in placebo recipients, corresponding to 96.7% vaccine efficacy against severe COVID-19.

The data came from the global Phase III trial (NCT04368728) assessing the vaccine. The ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy study enrolled 44,165 ≥16-year-old participants and 2,264 12-15-year-old participants who were randomized to receive 2 doses, 21 days apart, of 30 µg BNT162b2 or placebo.

20M Doses for Argentina—Argentina’s Health Minister Carla Vizzotti told reporters July 27 that her government agreed to acquire 20 million doses of the Pfizer/BioNTech COVID-19 vaccine for delivery this year: “The final agreement that remains is based on logistical issues to start the delivery schedule.” Argentina acted after complaining of delays in the delivery of doses of Russia’s Sputnik V vaccine.

As of July 21, 104,105 people had died of COVID-19 in Argentina , while 6.1 million people in the country had received both vaccine shots; the country’s population was estimated by the United Nations to be 45.6 million as of July 1.

Effectiveness vs. Delta Falls to 39%—A report released July 23 by Isarel’s Ministry of Health found the Pfizer/BioNTech COVID-19 vaccine to be 39% effective in preventing infections of the Delta variant of SARS-CoV-2 between June 20 and July 17—well below the 64% effectiveness reported between June 6 and July 3, and 94.3% between May 2 and June 5. However, the vaccine was found to be 88% effective in preventing hospitalizations and 91% effective in preventing severe Delta infection. According to the Ministry, more than 5.75 million Israelis (61.6% of total population) have received the first dose of the vaccine, with 5.28 million of these also receiving the second dose.

200M More U.S. Doses—Pfizer and BioNTech said July 23 that the U.S. government had purchased an additional 200 million doses of the Pfizer-BioNTech COVID-19 Vaccine for an undisclosed price, bringing the total number of doses to be supplied by the companies to the U.S. government to 500 million. The companies expect to deliver 110 million of the additional doses by December 31, 2021, with the remaining 90 million doses to be delivered no later than April 30, 2022, the companies said.

The U.S. government also has the option to acquire an updated version of the vaccine to address potential variants as well as new formulations of the vaccine as they become available and authorized.

Antibodies Boosted by Longer Interval Between Doses—Researchers from several U.K. universities on July 23 posted a preprint study showing that among 503 healthcare workers, those who had a “long” interval between their first and second doses of BNT162b2 (6–14 weeks, average of 70 days) showed higher levels of neutralizing antibodies compared to those with a “short” interval (3–4 weeks, average of 24 days) between doses—with a 2-4 fold increase in titer, depending on the variant tested—though the drop in antibody levels between doses was significant. Antibody levels were measured a month after the second dose. Also, neutralizing antibody levels against the Delta variant were poorly induced after a single dose, and not maintained during the interval before the second dose.

The Protective Immunity from T cells to COVID-19 in Health workers study (PITCH) assessed the effect of the vaccine on three SARS-CoV-2 variants—beta (B.1.351), gamma (P.1) and delta (B.1.167.2)—as well as the ancestral early pandemic virus (Victoria) in the 503 healthcare workers, of which 223 (44%) had previously had COVID-19.

While T cells were well-maintained between the first and second dose, overall T cell levels after two doses were 1.6 times lower after the long compared with the short dosing schedule. However, after the longer dosing interval, a higher proportion of T cells present were ‘helper’ T cells, which are important for long-term immune memory and helping generate antibodies to prevent infection.

BNT162b2, AstraZeneca Vaccines Effective vs. Delta—In a study published July 21 in The New England Journal of Medicine, a team of U.K. researchers reported that two doses of Pfizer/BioNTech’s BNT162b2 were 88% effective at preventing symptomatic disease from the delta variant of SARS-CoV-2, compared to 93.7% against the alpha variant. AstraZeneca’s COVID-19 vaccine showed a two-dose effectiveness of 74.5% among persons with the alpha variant and 67% among those with the delta variant.

Both vaccines showed similarly low effectiveness against the delta variant after one dose (30.7%), but effectiveness rose to 48.7% against the alpha variant after a single dose.

African Union Distribution Agreement—Pfizer and BioNTech said July 21 that they signed a letter of intent with The Biovac Institute, a CapeTown, South Africa biopharmaceutical company, to manufacture the Pfizer-BioNTech COVID-19 vaccine for distribution within the African Union. Under the agreement, whose value was not disclosed, Biovac agreed to perform manufacturing and distribution activities within Pfizer’s and BioNTech’s global COVID-19 vaccine supply chain and manufacturing network, which expanded as a result to three continents and more than 20 manufacturing facilities. To facilitate Biovac’s involvement in the process, technical transfer, on-site development and equipment installation activities will begin immediately, Pfizer and BioNtech said.

Pfizer and BioNTech said that expect Biovac’s Cape Town facility to be incorporated into their vaccine supply chain by the end of 2021. Biovac agreed to obtain drug substance from facilities in Europe, with manufacturing of finished doses set to begin in 2022. At full operational capacity, the annual production will exceed 100 million finished doses annually. All doses will exclusively be distributed within the 55 member states that make up the African Union, the companies added.

COMIRNATY Outperforms CoronaVac—In a study of 1,442 healthcare workers from public and private hospitals and medical clinics in Hong Kong, participants dosed with COMIRNATY—marketed in Greater China by Fosun Pharma and BioNTech—showed 10 times the amount of antibodies as were seen in patients dosed with Sinovac’s CoronaVac vaccine, a team of Hong Kong-based researchers reported in a study published July 25 in The Lancet.  

After their second dose, the geometric mean PRNT50 titre of COMIRNATY-dosed participants was 269 and the geometric mean PRNT90 titre was 113, compared with a geometric mean PRNT50 titre of 27 and a geometric mean PRNT90 titre was 8·4 in a subset of 12 participants dosed with CoronaVac, following low antibody concentrations after their first doses, as measured by ELISA and sVNT, rising to moderate concentrations after the second dose. 

“The difference in concentrations of neutralising antibodies identified in our study could translate into substantial differences in vaccine effectiveness,” concluded the research team, led by corresponding author Benjamin John Cowling, PhD, Professor and Division Head, Division of Epidemiology and Biostatistics at The University of Hong Kong. 

FDA Priority Review for Vaccine BLA—Pfizer and BioNTech said July 16 that the FDA had granted its Priority Review designation for the Biologics License Application (BLA) filed for the companies’ vaccine to prevent COVID-19 in individuals 16 years of age and older. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in January 2022. The companies completed the rolling submission of their BLA in May 2021.

Testing Effectiveness vs. Delta—Pfizer and BioNTech said July 8 they were conducting preclinical and clinical tests to confirm their hypothesis that a third dose of BNT162b2 will boost antibody titers against the Delta variant of SARS-CoV-2 (B.1.617.2 lineage, identified in India) 5 to 10 times higher than after two primary doses—a level similar to how a third dose has performed against the Beta variant of SARS-CoV-2 (B.1.351, identified in South Africa), as well as the wild type of the virus. The companies cited a study published June 10 in Nature showing that immune sera obtained shortly after dose 2 of the vaccine generated strong neutralization titers against the Delta variant in lab tests.

Lower Antibody Levels vs. Delta (India) Variant–In people fully vaccinated with two doses of the Pfizer/BioNTech vaccine, levels of neutralising antibodies were more than five times lower against the B.1.617.2 (Delta or India) variant compared to the original strain, a team of U.K. researchers reported June 3 in The Lancet. Antibody response was lower in people who had only received one dose. After a single dose of Pfizer-BioNTech, 79% of people had a quantifiable neutralizing antibody response against the original strain, which fell to 50% for the Alpha or U.K. variant B.1.1.7, 32% for Delta/India, and 25% for the Beta/South Africa variant.

As part of the SARS-CoV-2 Legacy study, led by the Francis Crick Institute and partners at University College London and UCL Hospitals NHS Foundation Trust, healthcare workers and staff from the institutions have donated blood and swab samples so that researchers can track changing risk of infection and response to vaccination. Within days of having enough of each variant to study, researchers were able to analyse antibodies in the blood of 250 healthy people who received either one or two doses of the Pfizer-BioNTech Covid-19 vaccine, up to three months after their first dose.

Researchers assessed the neutralizing antibodies generated by the Alpha, Beta, and Delta variants, as well as the orginal Wuhan strain and the D6146 strain dominant in Europe during the first wave of COVID-19 in April 2020.

EUROPEAN CMA EXPANDS TO ADOLESCENTS—The European Commission on May 28 granted an expanded Conditional Marketing Authorization (CMA) to Pfizer and BioNTech allowing the use of COMIRNATY in patients ages 12-15. The expanded CMA, valid in all 27 E.U. states, followed the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issuing a positive opinion to authorize the vaccine in that age group.

The E.C. based its decision on data from a pivotal Phase III clinical trial, which enrolled 2,260 participants aged 12 to 15 years. Participants received two 30 μg doses of the COVID-19 vaccine. Results from this trial, published in The New England Journal of Medicine on May 27, showed a vaccine efficacy of 100% in participants with or without prior SARS-CoV-2 infection and robust antibody responses. The vaccine was also generally well tolerated. Participants will continue to be monitored for long-term protection and safety for an additional two years after their second dose, Pfizer and BioNTech said.

A pediatric study evaluating the safety and efficacy of the companies’ COVID-19 vaccine in children 6 months to 11 years of age is ongoing. Pfizer and BioNTech said they expect to have definitive readouts and, subject to the data generated, submit for an Emergency Use Authorization in the U.S. or a variation to Conditional Marketing Authorizations in the E.U. for two cohorts, including children 2-5 years of age and 5-11 years of age, in September. The readout and submission for the cohort of children 6 months to 2 years of age are expected in the fourth quarter.

Up to 1.8B Additional Doses for E.U.—Pfizer and BioNTech said May 20 they agreed with the European Commission to supply the E.U. with 900 million additional doses of COMIRNATY®, with an option for the EC to request a further 900 million doses.

The additional 900 million doses are expected to be delivered on a monthly schedule beginning December 2021 and continuing into 2023. The new agreement comes in addition to the 600 million doses that had already been committed to the E.U. through 2021. All doses for the E.U. are planned to be manufactured within the E.U., Pfizer and BioNTech said.

Worldwide, the companies said, they believe they can manufacture at least 2.5 billion doses of the vaccine by year’s end, with the potential to produce up to 3 billion doses.

60M More Doses for Turkey—Pfizer and BioNTech said May 20 it entered into an agreement with Turkey’s Ministry of Health to supply 60 million additional doses of the companies’ COVID-19 vaccine, with an option for an additional 30 million doses. On December 25, 2020, the companies announced an initial agreement to provide 30 million doses of their vaccine to Turkey. The second supply agreement brings the total number of doses to be supplied to Turkey to up to 120 million, all of which will be delivered in 2021.

$40M Ireland Investment—Pfizer said May 20 it will invest $40 million to produce its COVID-19 vaccine at its Grange Castle site in Dublin, in addition to €300 million ($365 million) the company said last year it would spend at three Irish manufacturing sites. The company plans to create 75 jobs at the site when it begins production, which is expected around the end of 2021.

CDC OKs Vaccine for Adolescents—The U.S. Centers for Disease Control and Prevention (CDC) said May 12 it recommends use of the Pfizer/BioNTech COVID-19 vaccine among adolescents ages 12-15 immediately. CDC Director Rochelle Walensky, MD, MPH said she adopted a recommendation made by the agency’s Advisory Committee on Immunization Practices’ (ACIP).

FDA EXPANDS EUA TO ADOLESCENTS AGES 12-15—The FDA on May 10 expanded the emergency use authorization (EUA) of the Pfizer/BioNTech COVID-19 Vaccine to include adolescents ages 12-15. The agency based its decision on favorable safety and efficacy data from 2,260 participants ages 12-15 years old enrolled in an ongoing randomized, placebo-controlled clinical trial in the U.S., all of whom showed no evidence of prior infection with SARS-CoV-2.

Seven days after the second dose was administered to 1,005 vaccine recipients, the vaccine showed itself 100% effective in preventing COVID-19, while 16 cases of COVID-19 occurred among 978 placebo recipients. Immune response of 190 12-15-year-old to the vaccine was non-inferior to the immune response of 17- participants ages 16-25, the FDA said.

Rolling BLA Submission Begins—Pfizer and BioNTech said May 7 that they have initiated a BLA with the FDA for full approval of their Pfizer-BioNTech COVID-19 Vaccine to prevent COVID-19 in people ages 16 and older. Data to support the BLA will be submitted on a rolling basis over coming weeks, the companies said, followed by their request for Priority Review.

Pfizer and BioNTech have submitted nonclinical and clinical data, including the most recent analyses from their pivotal Phase III clinical trial, where the vaccine’s efficacy and favorable safety profile were observed up to six months after the second dose. The companies said they will submit the required manufacturing and facility data for licensure “in the coming weeks.”

Pfizer and BioNTech have also submitted an application to expand the current EUA for their COVID-19 vaccine to include individuals ages 12-15. The companies said they intend to submit a supplemental BLA covering that age group once the required data six months after the second vaccine dose are available.

As of May 7, the companies said, they have delivered more than 170 million doses of the vaccine across the U.S.

PFIZER REPORTS $3.462B IN Q1 SALES—Pfizer reported $3.462 billion in Q1 sales for the COVID-19 vaccine it co-developed with BioNTech. That figure includes $2.038 billion generated in the U.S., and $1.424 billion in total international revenues—consisting of $841 million in “Developed Europe” (Western Europe, Scandinavian countries and Finland); $513 million in “Emerging Markets” (includes, but is not limited to, Asia excluding Japan and South Korea, Eastern Europe, Latin America, Central Europe, the Middle East, Africa, and Turkey); and $70 million in “Developed Rest of the World” (Japan, Canada, Australia, South Korea and New Zealand).

The company also raised its guidance to investors on 2021 revenues for the vaccine to approximately $26 billion, up from approximately $15 billion, reflecting 1.6 billion doses expected to be delivered based on signed contracts as of mid-April.

European CMA Sought for Adolescent Use–Pfizer and BioNTech on April 30 said they submitted to the European Medicines Agency (EMA) a request to extension their Conditional Marketing Authorization (CMA) in the European Union (EU)  for COMIRNATY® (BNT162b2) allowing its use in adolescents 12 to 15 years of age.

The submission is based on positive Phase III data in 2,260 adolescents ages 12-15 showing a vaccine efficacy of 100% in participants with or without prior SARS-CoV-2 infection and robust antibody responses. Participants will continue to be monitored for long-term protection and safety for an additional two years after their second dose, the companies said.

Also on April 30, British researchers published a study in Science on April 30 showing that people with previous mild or asymptomatic COVID-19 had significantly enhanced protection against the U.K. (B.1.1.7) and South Africa (B.1.351) variants after a single dose of the Pfizer/BioNTech vaccine. However, lower levels of neutralizing antibodies were seen after a first dose in people without prior infection, potentially leaving them at risk from variants, according to the study, led by researchers from Imperial College London, Queen Mary University of London, and University College London.

In a separate study posted April 30 in a preprint, the ISARIC4C (Coronavirus Clinical Characterisation Consortium), a UK-wide consortium of doctors and scientists, found that the vast majority of post-vaccination cases of COVID-19 and deaths from the virus occurred in frail elderly patients following vaccination with a first dose of either the Pfizer/BioNTech or AstraZeneca vaccines: 526 cases including 113 deaths from 3,598 patients vaccinated out of 52,280 hospitalized COVID-19 patients studied. The study has been submitted to the U.K. government’s Scientific Advisory Group for Emergencies (SAGE) panel.

BNT162b2 and Moderna’s COVID-19 Vaccine (mRNA-1273) protect against COVID-19-related hospitalization among adults 65 years and older, according to a new U.S. Centers for Disease Control (CDC) assessment. The CDC said fully vaccinated adults ages 65+ were 94% less likely to be hospitalized with COVID-19 than people of the same ages who were not vaccinated, while partially-vaccinated people ages 65+ were 64% less likely to be hospitalized with COVID-19 than people who were not vaccinated.

The data constituted the first real-world findings in the U.S. confirming clinical trial data showing mRNA vaccines prevent severe COVID-19, the CDC said.

The CDC assessment examined hospitalizations in two U.S. hospital networks covering 24 hospitals in 14 states. Vaccine effectiveness was assessed by comparing the odds of COVID-19 vaccination among hospitalized people who tested positive for the virus that causes COVID-19 vs. control patients who tested negative. Among 417 participants in the assessment, there were 187 COVID-positive patients and 230 controls. Nearly half of the patients were more than 75 years old.

100M More Doses for EU—BioNTech and Pfizer said April 19 that they will supply an additional 100 million doses of COMIRNATY® to the 27 European Union (EU) member states in 2021, a result of the European Commission’s (EC) decision to exercise its option to purchase an additional 100 million doses under its expanded Advanced Purchase Agreement signed on February 17. This brings the total number of doses to be delivered to the EU to 600 million.

Pfizer CEO Albert Bourla, DVM, PhD, told CNBC’s Bertha Coombs at an event with CVS Health that people are “likely” to need a booster dose of a COVID-19 vaccine—BNT162b22 and other vaccines—within 12 months of getting fully vaccinated, and may need vaccination against the coronavirus annually.

“A likely scenario is that there will be likely a need for a third dose, somewhere between six and 12 months and then from there, there will be an annual revaccination, but all of that needs to be confirmed. And again, the variants will play a key role,” Bourla said in comments taped April 1 but televised April 15.

Faster Than Planned—Pfizer CEO Albert Bourla, DVM, PhD, said in an April 13 tweet that the company “can deliver 10% more doses to the US by the end of May than previously agreed,” for a total of 220 million. Bourla added that Pfizer “can supply the full 300M agreed on for the end of July two weeks early.”

EXPANDED EUA SOUGHT FOR 12-15 YEAR OLDS—Pfizer and BioNTech said April 9 that they requested the FDA amend their U.S. Emergency Use Authorization (EUA) for BNT162b2 allowing for expanded use in adolescents 12-15 years of age. Similar requests will be made to regulatory agencies worldwide, the companies added.

The requests, Pfizer and BioNTech said, will be based on positive Phase III data reporting 100% efficacy and robust antibody response for the vaccine in adolescents 12 to 15 years of age with or without prior evidence of SARS-CoV-2 infection, which the companies announced March 31. The FDA is expected to decide on the request in a few weeks, and is not expected to seek a recommendation from an advisory committee, as occurred before the EUA was granted in December 2020, The Wall Street Journal reported, citing an unnamed source.

Also on April 9, Australia’s government said it finalized an agreement to purchase 20 million additional doses of the vaccine, raising the country’s supply to 40 million doses—and effectively reversing earlier plans to rely heavily on AstraZeneca’s COVID-19 vaccine, 50 million doses of which were once envisioned as being manufactured within the country via partner CSL.

On April 5, Pfizer told Reuters that it was in talks with Israel’s government to supply additional doses beyond the undisclosed number already supplied under a November agreement whose value according to the country’s Finance Ministry was NIS 2.6 billion ($785 million).

The company would not confirm a report in The Jerusalem Post stating that a shipment of 700,000 doses was set to arrive in Israel on April 4, but was halted after the government failed to approve transfer of payment for a previous 2.5 million doses supplied by Pfizer and BioNTech, due to a political squabble that forced cancellation of a cabinet meeting.

Pfizer and BioNTech on April 1 released updated topline results from an analysis of 927 confirmed symptomatic cases of COVID-19 seen in their pivotal Phase III study (NCT04368728) through March 13, showing that BNT162b2 was 91.3% effective against COVID-19, measured seven days through up to six months after the second dose. The vaccine was 100% effective against severe disease as defined by the U.S. Centers for Disease Control and Prevention (CDC), and 95.3% effective as defined by the FDA.

From the 927 confirmed symptomatic cases of COVID-19 in the trial, 850 cases of COVID-19 were in the placebo group and 77 cases were in the BNT162b2 group. Thirty-two cases of CDC-defined severe disease were seen in the placebo group vs. none in the BNT162b2 vaccinated group. Twenty-one FDA-defined severe cases were observed in the placebo group vs. one case in the BNT162b2 vaccinated group.

In the U.S., a total of 697 cases of COVID-19 were seen, of which 647 were in the placebo group vs. 50 in the vaccine group. In South Africa, where the B.1.351 lineage is prevalent and 800 participants were enrolled, nine cases of COVID-19 were observed, all in the placebo group, Pfizer and BioNTech said.

On March 31, Pfizer and BioNTech said they planned to seek expansions of their Emergency Use Authorization of BNT162b2 and EU Conditional Marketing Authorization for COMIRNATY® allowing for their use in adolescents 12-15 years of age as soon as possible. They cited positive data for BNT162b2 showing 100% efficacy and robust antibody responses in vaccinated participants ages 16-25 years old, and was well tolerated, according to topline results from a pivotal Phase III trial assessing the vaccine in 2,260 U.S. adolescents.

Eighteen cases of COVID-19 were seen in 1,129 placebo patients, vs. none among 1,131 vaccinated patients. BNT162b2 elicited SARS-CoV-2–neutralizing antibody geometric mean titers (GMTs) of 1,239.5, demonstrating strong immunogenicity in a subset of adolescents one month after the second dose—comparable to the 705.1 GMTs elicited by participants aged 16-25 years old in an earlier analysis, BioNTech and Pfizer said.

The European Medicines Agency (EMA) said March 26 that its Committee for Medicinal Products for Human Use (CHMP) recommended approval of a new site in Marburg, Germany, as a fourth site for the production of the vaccine, marketed in Europe as COMIRNATY. The facility will produce both active substance and finished product. The CHMP has also given a positive opinion to allow transportation and storage of vials of the vaccine at temperatures between -25 to -15˚C for two weeks, as an alternative to the long-term storage of the vials at a temperature between -90 to -60˚C in special freezers. The EMA said the change is expected to facilitate the rapid roll-out and distribution of the vaccine in the EU by reducing the need for ultra-low temperature cold storage conditions.

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:

● ANTIVIRAL
● VAX
● ANTIBODY
● RNA