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1109 Pfizer Vaccine Efficacy
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New bar set by BioNTech, Pfizer COVID-19 vaccine could see swift influx of challengers

The strong start for COVID-19 vaccines could be quickly followed by more data as infection rates soar

The strong start for COVID-19 vaccines could be quickly followed by more data as infection rates soar.

Nov 10, 2020 | 2:44 AM GMT

With interim COVID-19 vaccine efficacy data from BioNTech and Pfizer outstripping the field’s expectations, the results have set a high bar for what could be a rapid wave of readouts accelerated by surges in case counts.

The data shared by BioNTech SE (NASDAQ:BNTX) and Pfizer Inc. (NYSE:PFE) Monday represent both a rising tide that lifts all boats, and a sea level change that could potentially sink other candidates.

Recent climbs in infections across the U.S., Europe and South America — which saw the trial jump from under 32 COVID-19 cases on Oct. 27 to 94 cases in less than two weeks — could mean competing data might soon be available from other companies with late-stage trials. Moderna Inc. (NASDAQ:MRNA) is expected to provide data soon on its vaccine, which uses a similar mRNA technology; the company said it would release interim efficacy data once 53 COVID-19 cases were observed.

An interim analysis conducted by an independent data monitoring committee showed Pfizer and BioNTech’s BNT162b2 had an efficacy rate above 90% in the 94 COVID-19 cases identified among 38,955 trial participants who received two doses of the vaccine as of Nov.  8.

While the companies did not release information about the demographics of the cases, the severity of their symptoms or the cohorts they belonged to, the reported efficacy rate indicates that fewer than nine of the cases came from the group that received the vaccine.

The results are the clearest signal to date that SARS-CoV-2 infection can be effectively countered by vaccines. The lack of approved vaccines for any human coronaviruses, and the decades of failure in HIV vaccination despite large-scale worldwide initiatives, served as acute reminders this outcome was not a foregone conclusion.

Pfizer and BioNTech’s data also provide the first proof of concept for BNT162b2’s molecular target, the SARS-CoV-2 spike protein, and its therapeutic modality, mRNA. 

If BNT162b2’s high rate of protection is maintained through the trial’s final analyses, other companies may find it difficult to compete if their candidates only meet the field’s original expectations. BioNTech and Pfizer, Moderna, AstraZeneca plc (LSE:AZN; NASDAQ:AZN) and Johnson & Johnson (NYSE:JNJ) all set the bar for their final analyses at around 50% protection in over 150 patients.

Scrutiny will be particularly rigorous for other RNA vaccines, such as Moderna’s mRNA-1273, because the emerging modality lacks prior approvals and its cold chain distribution requirements add logistical hurdles. Vaccines with more established modalities, such as Novavax Inc. (NASDAQ:NVAX)’s protein-based NVX-CoV2373 or inactivated viral vaccine PiCoVacc from Sinovac Biotech Ltd. (NASDAQ:SVA) could have more room to compete, even with a lower rate of efficacy.

Because BioNTech and Pfizer limited their analysis to symptomatic patients and did not conduct routine COVID-19 screening tests, the results shed no light on the vaccine’s capacity to prevent asymptomatic disease, a key driver of the disease’s spread. 

The partners will report their final analysis once the trial reaches 164 confirmed cases. The companies anticipate they will apply for emergency use authorization (EUA) soon after reaching FDA’s requirement for a median of two months of safety data next week.

Pfizer projects it will produce 50 million doses of BNT162b2 in 2020, and 1.3 billion doses in 2021.

First look at protection

The primary endpoint in Pfizer and BioNTech’s pivotal trial measures confirmed COVID-19 cases that accrue starting seven days after the second vaccine dose in individuals who did not present evidence of infection at baseline. A reduction in this endpoint compared with placebo indicates the vaccine is protective 28 days after individuals start the two-dose regimen.

The companies also plan to evaluate a secondary endpoint of COVID-19 cases accruing starting 14 days after the second dose, to enable comparisons with other trials that use the later endpoint, including Moderna’s. 

Pfizer said “no serious safety concerns” had been observed, and plans to release detailed Phase III data in a peer-reviewed publication.

The company’s definition of what counts as a confirmed COVID-19 case limited the scope of its conclusions to patients who could identify that they were sick.

The trial protocol specifies that cases are counted if a patient displays at least one disease symptom, and if the virus is detected via a reverse transcription polymerase chain reaction (RT-PCR) tests, either during the symptomatic period, or within the four days before or after. 

The partners had initially planned to release interim data once the trial reached 32 cases, which would have required 76.9% efficacy to be deemed successful, but switched to a 62 case trigger point after discussions with FDA. By the time the discussions concluded, that threshold had been exceeded.

Pfizer and BioNTech have enrolled a total of 43,538 participants in the trial, 42% of which they said had diverse backgrounds.

RNA rivalry

BNT162b2 and Moderna’s mRNA-1273’s shared molecular target, therapeutic modality and development timeline have made it challenging to predict whether either one will have an advantage in the clinic.

Early-stage analyses of neutralizing antibody titers induced by each vaccine shed little light on relative performance due to the lack of harmonization in virus neutralization assays. In these studies, Pfizer and BioNTech disclosed more data about T cell responses than Moderna, and the limited data available suggest the former companies may have an advantage when it comes to inducing CD8+ T cells.

More illuminating are studies of age-dependent differences in neutralizing antibody titers for the same vaccine; Moderna’s candidate appeared to work similarly well across age groups, while BioNTech saw weaker efficacy in older participants.

Both BNT162b2 and mRNA-1273 encode the same spike protein variants, with identical amino acid sequences. That makes their respective lipid nanoparticle formulations the main potential source of difference in their composition.

Different lipid nanoparticle formulations could distinguish how the two vaccines activate the innate immune system, which could impact both efficacy and safety.

The vaccines’ formulations also determine their storage requirements. While Moderna’s vaccine can be stored in standard -20° Celsius freezers, Pfizer and BioNTech’s vaccine requires storage at -80° Celsius, which is a greater logistical challenge.

While both clinical trial’s endpoints are based on reduction in symptomatic disease, Moderna has disclosed that it plans to study the rate of asymptomatic cases in its trial population using serological assays that detect antibodies against the virus’ nucleocapsid protein, which is not encoded by the vaccine, and the antibodies are therefore more likely to have been induced by an infection. 

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