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Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report
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https://www.medrxiv.org/content/10.1101/2020.06.30.20142570v1
Abstract
In March 2020, the WHO declared a pandemic of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 With >8.8 million cases and
>450,000 deaths reported globally, a vaccine is urgently needed. We report the available safety, tolerability, and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose escalation study among healthy adults, 18-55 years of age, randomized to receive 2 doses, separated by 21 days, of 10 μg, 30 μg, or 100 μg of BNT162b1, a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titers in sera
increased with dose level and after a second dose. Geometric mean neutralizing titers reached 1.8- to 2.8-fold that of a panel of COVID-19 convalescent human sera. These results support
further evaluation of this mRNA vaccine candidate.
Discussion
The RNA-based SARS-CoV-2 vaccine candidate BNT162b1 administered at 10 g, 30 g, and
100 g to healthy adults 18-55 years of age exhibited a tolerability and safety profile consistent
with those previously observed for mRNA-based vaccines.5 A clear dose-level response was
observed after Doses 1 and 2 in adults 18-55 years of age. Based on the tolerability profile of the
first dose at the 100 μg dose level and the second dose of 30 μg, participants randomized to the
100 μg group did not receive a second vaccination. Reactogenicity was generally higher after
the second dose in the other two dosing levels, however symptoms were transient and resolved
within a few days. Transient decreases in lymphocytes (Grades 1-3) were observed within a few
days after vaccination, with lymphocyte counts returning to baseline within 6-8 days in all
participants. These laboratory abnormalities were not associated with clinical findings. RNA
vaccines are known to induce type I interferon which has been associated with transient
migration of lymphocytes into tissues.15, 16, 17,18
Robust immunogenicity was observed after vaccination with BNT162b1. RBD-binding IgG concentrations were detected at 21 days after the first dose and substantially increased 7 days
after the second dose given at Day 21. After the first dose, the RBD-binding IgG GMCs (10 μg
dose recipients) were similar to those observed in a panel of 38 convalescent, human serology
samples obtained at least 14 days after PCR-confirmed following SARS-CoV-2
infection/COVID-19 asymptomatic donors. Post-dose 1 GMCs were similar to those of the 30 μg
and 100 μg groups but substantially higher than those in the convalescent serum panel. After
Dose 2 with 10 μg or 30 μg BNT162b1, the RBD-binding IgG GMCs were ~8.0-fold to ~50-fold
that of the convalescent serum panel GMC.
Neutralization titers were measurable after a single vaccination at Day 21 for all dose levels. At
Day 28 (7 days after Dose 2), substantial SARS-CoV-2 neutralization titers were observed. The
virus neutralizing GMTs after the 10 μg and 30 μg Dose 2 were, respectively, 1.8-fold and 2.8-
fold the GMT of the convalescent serum panel. Assuming that neutralization titers induced by
natural infection provide protection from COVID-19 disease, comparing vaccine-induced SARSCoV-
2 neutralization titers to those from sera of convalescent humans quantifies the magnitude
of the vaccine-elicited response and the vaccine's potential to provide protection. Since the 100
μg dose level cohort was not boosted, no corresponding data for immunogenicity after a second
vaccination are available however there were no substantial differences in immunogenicity
between the 30 μg and 100 μg dose levels after Dose 1. This observation suggests that a well-
tolerated and immunogenic dose level may be between 10 μg and 30 μg for this vaccine
candidate.
Our study had several limitations. While we used convalescent sera as a comparator, the kind of
immunity (T cells versus B cells or both) and level of immunity needed to protect from COVID-
19 are unknown. Further, this analysis of available data did not assess immune responses or
safety beyond 2 weeks after the second dose of vaccine. Both are important to inform the public
health use of this vaccine. Follow-up will continue for all participants and will include collection
of serious adverse events for 6 months, and COVID-19 infection and multiple additional
immunogenicity measurements through up to two years. While our population of healthy adults
55 years of age and younger is appropriate for a Phase 1/2 study, it does not accurately reflect the
population at highest risk for COVID-19. Adults 65 years of age and over have already been
enrolled in this study and results will be reported as they become available. Later phases of this
study will prioritize enrollment of more diverse populations, including those with chronic
underlying health conditions and from racial/ethnic groups adversely affected by COVID-19.19
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.
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The company said one of its four coronavirus vaccine candidates produced neutralizing antibodies, which researchers believe is necessary to build immunity to the virus, in all participants who received two of the 10 or 30 microgram doses after 28 days, according to the preliminary data. The findings were posted in a paper released on MedRXiv. The company said the levels of neutralizing antibodies were 1.8 to 2.8 times higher than in recovered Covid-19 patients.
After 28 days, all participants in the two lower-dose groups had significant levels of binding antibodies, the company said.
"We are encouraged by the clinical data of BNT162b1, one of four mRNA constructs we are evaluating clinically, and for which we have positive, preliminary, topline findings," Kathrin Jansen, head of Pfizer's vaccine research and development, said in a press release. "We are dedicated to develop potentially groundbreaking vaccines and medicines, and in the face of this global health crisis, we approach this goal with the utmost urgency."
The findings posted Wednesday have not been peer-reviewed yet.
The effort by Pfizer and BioNTech is one of several working on a potential vaccine to prevent Covid-19, which has infected more than 10 million people worldwide and killed at least 511,851, according to data compiled by Johns Hopkins University. There are more than 100 vaccines currently under development, according to the World Health Organization.
Another leading vaccine candidate from biotech firm Moderna is expected to enter a late-stage trial later this month, pending the results from its mid-stage trial. If all goes well in Moderna's next trial, its vaccine could be available for public distribution by the end of the year.
The U.S.-based pharmaceutical giant has been working alongside German drugmaker BioNTech. The companies' experimental vaccine contains genetic material called messenger RNA, or mRNA. The mRNA is a genetic code that tells cells what to build — in this case, an antigen that may induce an immune response to the virus.
Pfizer said the vaccine was generally well tolerated, though the experimental vaccine caused fever in some patients, especially for those who were in the 100 microgram group. Most patients reported pain at the injection site, which was mild to moderate, the company said, except in one of 12 subjects who received a 100 microgram dose, which was severe.
https://www.cnbc.com/2020/07/01/pfizer-stock-jumps-after-it-reports-positive-data-in-early-stage-coronavirus-vaccine-trial.html
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Covid-19 vaccine from Pfizer and BioNTech shows positive results
July 1, 2020
https://www.statnews.com/2020/07/01/covid-19-vaccine-from-pfizer-and-biontech-shows-positive-results/
An experimental Covid-19 vaccine being developed by the drug giant Pfizer and the biotech firm BioNTech spurred immune responses in healthy patients, but also caused fever and other side effects, especially at higher doses.
The first clinical data on the vaccine were disclosed Wednesday in a paper released on medRXiv, a preprint server, meaning it has not yet been peer-reviewed or published in a journal.
"We still have a ways to go and we're testing other candidates as well," said Philip Dormitzer, the chief scientific officer for viral vaccines at Pfizer's research laboratories. "However, what we can say at this point is there is a viable candidate based on immunogenicity and early tolerability safety data."
The study randomly assigned 45 patients to get one of three doses of the vaccine or placebo. Twelve received a 10-microgram dose, 12 a 30-microgram dose, 12 a 100-microgram dose, and nine a placebo. The 100-microgram dose caused fevers in half of patients; a second dose was not given at that level.
Following a second injection three weeks later of the other doses, 8.3% of the participants in the 10-microgram group and 75% of those in the 30-microgram group developed fevers. More than 50% of the patients who received one of those doses reported some kind of adverse event, including fever and sleep disturbances. None of these side effects was deemed serious, meaning they did not result in hospitalization or disability and were not life-threatening.
The vaccine generated antibodies against SARS-CoV-2, the virus that causes Covid-19, and some of these antibodies were neutralizing, meaning that they appear to prevent the virus from functioning. Levels of neutralizing antibodies were 1.8 to 2.8 times the level of that in the recovered patients.
It's not certain that higher antibody levels will lead to immunity to the virus. To prove that, Pfizer will need to conduct large studies that aim to prove that people who have received the vaccine are at least 50% less likely to become infected. Those studies are expected to begin this summer, mostly in the United States. Pfizer and BioNTech are testing four different versions of the vaccine, but only one will advance to larger studies.
The current study did not include pregnant women, and no other information on the ethnic diversity of participants was noted, although the paper does say that future studies will need to include a more diverse group.
The second dose, a booster shot, was required for immunity. The patients who received the single 100-microgram dose had lower antibody levels than those who received two shots of the lower doses.
Fourteen Covid-19 vaccines are currently in human trials, according to the Milken Institute, including entrants from Inovio, CanSino, AstraZeneca, and Moderna. More are expected to start soon, including entrants from Merck, Johnson & Johnson, and Sanofi. In total, 178 vaccines are in various stages of development.
The Pfizer/BioNTech vaccine, like the Moderna vaccine, is based on a technology called messenger RNA, which uses a key genetic messenger found in cells to create protein that the immune system then learns to attack. Moderna has not yet published data on its vaccine but is expected to do so soon.
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