New Pfizer/BioNTech COVID-19 Vaccine Data Confirm Prior Results, Show T-Cell Boost
Executive Summary
While data from small trials are difficult to compare, it appears that T-cell responses to BNT162b1 may be stronger than those reported so far for Moderna’s competing mRNA-based vaccine.
Pfizer Inc. and BioNTech SE released Phase I/II results for their messenger RNA (mRNA)-based COVID-19 vaccine candidate BNT162b1, from a clinical trial conducted in Germany, that showed T-cell responses that may be stronger than those observed with a competing mRNA vaccine from Moderna, Inc. The data are also consistent with neutralizing antibody data reported previously from a US study.
Pfizer and BioNTech reported results on 20 July from 60 German trial participants, including 12 patients each injected with 1mcg, 10mcg, 30mcg or 50mcg doses of BNT162b1 on days one and 22, or a single dose on day one of 6mcg. Among 46 patients receiving two doses of the vaccine, the companies said SARS-CoV-2 neutralizing antibodies were observed at day 43 at dose-dependent levels with geometric mean titers (GMTs) of 0.7 to 3.2 times the levels seen in convalescent human serum from 38 patients who recovered from SARS-CoV-2 infection.
The partners also said high levels of CD4-positive and CD8-positive T-cells against the SARS-CoV-2 receptor binding domain (RBD) were observed in many participants and at all dose levels, but not in a dose-dependent manner. The individuals who generated T-cells did so at levels higher than detected in convalescent sera from six recovered COVID-19 patients. The T-cells had “a favorable Th1 profile and the absence of a potentially deleterious Th2 immune response,” according to a study write-up published on the preprint server medRxiv.
Pfizer rose 0.7% to $36.50 per share and BioNTech closed up 3.5% at $88.20 on 20 July based on the latest round of BNT162b1 results, while Moderna’s stock closed down 12.8% at $82.68.
The University of Oxford and AstraZeneca PLC also reported Phase I results for their adenovirus-based vaccine against the novel coronavirus on 20 July, but analysts noted that GMT levels for a small group of patients who received two doses of the candidate known as AZD1222 were below those seen with Pfizer/BioNTech’s BNT162b1 and Moderna’s mRNA-1273.
Bernstein analyst Ronny Gal said Oxford/AstraZeneca’s AZD1222 looks less competitive because “1) the titers from immunized patients were lower than convalescent patients, whereas BioNTech and Moderna vaccines both elicited IgGs substantially higher than convalescent controls (but each company used different convalescent groups, so direct comparison is not possible), 2) even the prime boost group was at most even with convalescent patients (lower on some of the assays), 3) markers of cellular immunity are present, but not broken down between CD4 and CD8, peak early and decline, and the magnitude is difficult to interpret.”
Moderna Vaccine Generates More Antibodies, Fewer T-Cells
Moderna reported Phase I results from 45 people on 14 July. The company said that at day 57, in 15 trial participants injected with two 100mcg doses of mRNA-1273 on day one and day 28, geometric mean titers of neutralizing antibodies were 2.1 to 4.1 times higher than observed in convalescent serum from 38 recovered COVID-19 patients versus 0.7- to 3.2-fold increases that Pfizer and BioNTech are now reporting for their vaccine.
Moderna said its Phase I participants treated with two 25mcg and 100mcg doses generated T-cells but did not provide detailed T-cell response data. A same-day New England Journal of Medicine publication noted that the two doses “elicited CD4 responses that … were strongly biased toward expression of Th1 cytokines … with normal type 2 helper T-cell (Th2) cytokine expression.” The NEJM article said CD8-positive T-cells were “detected at low levels after the second vaccination in the 100mcg dose group.”
Investigators for the Phase I trial of Moderna’s mRNA-1273 also shed some light on the importance of Th1 versus Th2 T-cell responses in the NEJM paper, explaining that Th1-biased, CD8-positive T-cells protect against replication of the SARS-CoV-2 virus in the lungs and nose, whereas animal studies of coronavirus vaccines that generated Th2-biased T-cell responses showed that the animals experienced enhanced respiratory disease.
The results from Pfizer and BioNTech for BNT162b1 are particularly notable with regard to T-cell responses, because CD4-positive and CD8-positive T-cells were observed across all four dose groups in which patients received two injections – a prime and booster shot – of the vaccine. Out of 36 participants in which T-cell responses were evaluated, 34 had CD4-positive T-cells (94.4%) and 29 (80.6%) had CD8-positive T-cells on par with or above levels seen in convalescent serum.
Pfizer and BioNTech also noted that the CD8-positive T-cells observed with BNT162b1 treatment were comparable to memory T-cell responses observed against cytomegalovirus, Epstein Barr virus and influenza in the same individuals.
In contrast, Moderna showed CD4-positive T-cells in only two out of the three doses in its Phase I study and the levels of CD8-positive T-cells observed in the 100mcg dose group were described as low. Specific levels of T-cell generation and numbers of participants who generated T-cells were not disclosed. Moderna will test its 100mcg dose in its Phase III trial, which is expected to begin on 27 July.
Pfizer, BioNTech German Data Versus US Results
Data from the Phase I/II study of BNT162b1 in Germany compared favorably with the results Pfizer and BioNTech reported on 1 July from their Phase I/II trial in the US.
Antibodies that bind with the SARS-CoV-2 RBD were observed at day 28 in 12 participants treated with two injections of the 10mcg and 30mcg doses of the vaccine at eight and 46.2 times the geometric mean concentrations (GMCs) observed in convalescent serum. In the German study, antibodies that block binding with the RBD were observed at day 43 in patients treated with all four doses in which patients received two injections at GMC levels 6.5 to 30.4 times what was seen in convalescent serum.
There were no serious adverse events in the German study and as was seen in the US study, most adverse events were mild to moderate and transient, including systemic side effects and injection site reactions. Fatigue and headache were the most common adverse events, but some trial participants had severe flu-like symptoms, including fever, chills, headache, muscle pain and joint pain. Some people also had severe injection site pain and tenderness.
In both sets of severe events, symptoms resolved spontaneously and were managed with “simple measures,” according to the preprint article, including with over-the-counter pain medicines. Participants in the 60mcg dose group did not receive a second injection as a booster due to “reactogenicity” seen at the 50mcg dose level, the paper said.
Pfizer and BioNTech still are testing multiple vaccine candidates against SARS-CoV-2 in early studies in an effort to pick the best candidate and the right dose for their upcoming late-stage trial. The companies plan to begin a Phase IIb/III study with up to 30,000 trial participants in late July.
The partners are simultaneously investing in manufacturing capacity to product enough vaccine to meet global demand. Pfizer and BioNTech say that they will be able to manufacture 100 million doses by the end of 2020 and as much as 1.3 billion doses by the end of 2021. The companies will work jointly to distribute the vaccine worldwide, expect for in China where BioNTech has an agreement with Fosun Pharma.
Pfizer and BioNTech already are taking orders for their vaccine. The companies also announced on 20 July that they signed a deal to sell 30 million vaccine doses to the UK government.
Pfizer has said since April that if things go well, it could receive an emergency use authorization (EUA) from the US Food and Drug Administration in October. (Also see "An Ambitious COVID-19 Vaccine Development Plan For Pfizer And BioNtech" - Scrip, 28 Apr, 2020.) Vaccines candidates from Pfizer/BioNTech and Moderna are among the leaders in the race to bring a preventive treatment against COVID-19 to the commercial market. (Also see "COVID-19: The Race To Develop A Vaccine" - Scrip, 9 Jun, 2020.)
However, SVB Leerink analyst Geoffrey Porges said in a 20 July note on the COVID-19 vaccines pipeline that he is skeptical about the timelines laid out by companies that anticipated EUA approval from the US FDA by the end of 2020.
“While it is possible that the FDA may grant EUA approvals for vaccines for high-risk individuals with limited clinical data, it is very unlikely that such approval will be granted for widespread use in the healthy adult population,” Porges said. “It seems more likely that the first vaccine approval will become a political event, like the first test approval was, with the reality of the availability, effectiveness and utility of the vaccine falling far short of the promotion by government officials.”
“The FDA guidance document states that pivotal efficacy and safety studies need to include ‘many thousands’ of subjects, and contain observation for safety for at least six months post vaccination (and ideally subsequently followed for 1-2 years),” the analyst continued. “It is impossible for any of the current programs to fulfill the requirements of these guidelines and get approved by the end of 2020. Even with their highly aggressive, never-before-achieved pivotal trial timelines, the earliest they could have pivotal trial data matching the FDA’s guidance requirements will be in late Q1 2021.” (Also see "COVID-19 Vaccine Should Demonstrate At Least 50% Effectiveness, US FDA Says" - Pink Sheet, 30 Jun, 2020.)