Moderna’s COVID-19 Second Booster Authorization Largely Thanks To Pfizer/BioNTech Data
Executive Summary
Safety and effectiveness of an mRNA-1273 second booster dose was inferred in large part by extrapolation from reported evidence following use of the Pfizer/BioNTech COVID-19 vaccine in individuals 60 years and older in Israel, FDA review memos show.
The US Food and Drug Administration’s recent authorization of a second booster dose of Moderna, Inc.’s COVID-19 vaccine largely piggybacked on Israeli data specific to Pfizer Inc./BioNTech SE’s competing mRNA product.
“Safety and effectiveness of the Moderna COVID-19 vaccine second booster dose is inferred in large part by extrapolation from reported evidence following use of the Pfizer/BioNTech COVID-19 vaccine in individuals 60 years and older,” Center for Biologics Evaluation and Research director Peter Marks wrote in a review memo.
However, it is reasonable to extrapolate safety and effectiveness conclusions from use of the Pfizer/BioNTech vaccine as a second booster dose to inform an assessment of benefits and risks for use of the Moderna vaccine as a second booster, Marks said. “Both vaccines are mRNA vaccines encoding similar SARS-CoV-2 spike protein antigens, with similar safety and effectiveness reported from studies evaluating these vaccines when used as a first booster dose (homologous or heterologous) in individuals 18 years of age and older,” the memo states.
With applications for Pfizer’s and Moderna’s vaccines for children five and under now expected to be reviewed by FDA, the extent to which the agency relied on data extrapolation during this earlier review is notable. (Also see "Moderna COVID Vaccine EUA For Kids Younger Than Six Will Be Big Test For FDA Efficacy Threshold" - Pink Sheet, 28 Apr, 2022.)
On 28 March, the FDA granted emergency authorization for use of the Pfizer/BioNTech and Moderna vaccines as a second booster dose in individuals ages ≥50 years. The EUA for a second booster also encompasses immunocompromised individuals ≥12 years for the Pfizer/BioNTech vaccine (BNT162b2) and ≥18 years for the Moderna product (mRNA-1273). (Also see "US FDA Bypasses Adcomm In Authorizing Second COVID Booster Because Decision ‘Straight-Forward’" - Pink Sheet, 29 Mar, 2022.)
The authorized populations did not align with what had been formally requested by the vaccine sponsors. Pfizer/BioNTech sought authorization as a second booster only in individuals ≥65 years, while Moderna broadly sought authorization in all individuals ≥18 years. (Also see "Moderna’s Bid For Second COVID Vaccine Booster Spans Broader Age Group Than Pfizer/BioNTech" - Pink Sheet, 18 Mar, 2022.)
Separate review memos for the Pfizer/BioNTech and Moderna second booster authorizations cite studies by the US Centers for Disease Control and Prevention, Kaiser Permanente and United Kingdom that suggest waning of vaccine-induced protection with COVID-19 vaccines, including following first booster doses.
The totality of evidence from these studies “suggest that there is a reduction of protection against serious outcomes of COVID-19 following a first mRNA vaccine booster dose and that individuals who received primary vaccination and a homologous booster dose with the Janssen COVD-19 vaccine may have suboptimal protection against COVID-19 and associated hospitalizations due to the Omicron variant,” the FDA said.
Limited Evidence Heavily Reliant On Israel
The memos also reflect the limited evidence, particularly specific to the Moderna vaccine, supporting the authorization, as well as the FDA’s continued heavy reliance on the Israeli experience with BNT162b2 in its decision-making regarding mRNA vaccine boosters and safety.
On 2 January, Israel began a vaccination campaign with second booster doses of BNT162b2 in individuals ≥60 years and medical staff who received an initial booster at least four months earlier.
Both Pfizer/BioNTech and Moderna provided evidence from an open-label, clinical intervention trial conducted at Sheba Medical Center in Israel. A total of 154 and 120 participants ≥18 years received a second booster dose of BNT162b2 and mRNA-1273, respectively, at least four months after a first booster dose with BNT162b2.
For the Pfizer/BioNTech product, there were approximately 11-fold increases in geometric mean neutralizing antibody titers against wild-type virus, Delta and Omicron variants at two weeks after the second booster compared with five months after the first booster, the FDA said. For mRNA-1273, the GMT increases were approximately 11-fold, 16-fold and 7-fold for wild-type virus, Delta and Omicron, respectively.
The information specific to mRNA-1273 from this study “indicates indirect and limited evidence of clinical benefit from reported immunogenicity findings after a fourth (second booster) dose of Moderna COVID-19 vaccine,” the FDA said.
Israeli researchers reported that protection against confirmed Omicron infection appeared to peak in the fourth week after the second booster dose of BNT162b2, waning quickly thereafter. In contrast, protection against severe illness did not appear to decrease by the sixth week after receipt of the second booster.
Both sponsors also provided information from what was, at the time, a non-peer-reviewed preprint of an Israeli Ministry of Health study in approximately 1.2 million people ≥60 years eligible for a fourth dose of an mRNA vaccine. The authors reported that a second booster dose of BNT162b2 was associated with a 4.3-fold reduction in the rate of hospitalizations compared with those who had only received one booster dose, the FDA review memo states.
This Ministry of Health study was published in the New England Journal of Medicine on 5 April and presented by two of the authors at the following day’s meeting of the Vaccines and Related Biological Products Advisory Committee. The FDA convened the advisory committee for a high-level discussion on broader considerations for booster doses and the process for changing the composition of current vaccines to address emerging variants. (Also see "What Will Trigger Modification Of COVID-19 Vaccines?" - Pink Sheet, 7 Apr, 2022.)
Writing in the NEJM, Yinon Bar-On, Weizmann Institute of Science, and colleagues reported that compared with a single booster given at least four months earlier, a second booster (or fourth dose in total) “provides added short-term protection against confirmed infections and severe illness caused by the Omicron variant.”
“The incidence rate for confirmed infection was lower by a factor of 2 and the rate of severe disease lower by a factor of 3 among persons in the fourth week after receiving the fourth dose than among eligible persons who did not receive the fourth dose,” the NEJM article states.
However, the protection against confirmed Omicron infection appears to peak in the fourth week after the second booster, waning quickly thereafter. “In contrast, protection against severe illness did not appear to decrease by the sixth week after receipt of the fourth dose,” Bar-On, et al. said. “More follow-up is needed in order to evaluate the protection of the fourth dose against severe illness over longer periods.”
Potential Survival Benefit
The FDA review memos also cite a non-peer-reviewed study from Israel, published as a preprint after the EUA amendment requests were submitted, that included more than 563,000 individuals ages 60-100 years, some or all of whom potentially overlapped with the Ministry of Health study. Almost 329,000 (58%) of these individuals had received a second booster of BNT162b2.
“The authors reported that death due to COVID-19 occurred in 92 second-booster recipients and in 232 individuals who received one booster dose indicating an adjusted hazard ratio 0.22 (95% CI 0.17 to 0.28),” the FDA said.
In addition, Pfizer/BioNTech submitted with their EUA request information from predictive modeling that assumed another COVID case wave might occur, with the predicted number of cases during such a wave derived from the average number of cases during the Alpha, Delta and Omicron waves.
Based on these assumptions, the FDA said, it was predicted that for every 1 million booster doses given to individuals ≥65 years, over the course of four months the following would be prevented:
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5,112 symptomatic infections (range 1,536-10,220);
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1,144 hospitalizations (range 884-1,508); and
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468 deaths (range 352-612).
The agency concluded the totality of the evidence suggests a second booster dose of either mRNA vaccine, given at least four months after the first, would provide additional protection over previous vaccinations in preventing COVID-19 and associated serious outcomes, particularly hospitalization and death, with no new safety concerns identified.
“The duration of additional protection conferred by a second booster dose is unknown and may be subject to waning, similar to protection conferred by a first booster dose.” – FDA
Nevertheless, the agency cited a host of uncertainties with the data summarized in the memos. In addition to extrapolation of the BNT162b2 data to the Moderna vaccine, the agency noted some of the information cited was from non-peer-reviewed preprints, and most of the reported experience with waning effectiveness against hospitalization following a first booster dose and additional protection conferred by a second booster comes from outside the US.
In addition, “the duration of additional protection conferred by a second booster dose is unknown and may be subject to waning, similar to protection conferred by a first booster dose.”
At the VRBPAC meeting, Marks described the authorization of a second mRNA vaccine booster dose as a “stopgap” measure until plans are in place for a potential next booster with a different composition. (Also see "COVID-19 Vaccine Second Booster Authorization A ‘Stopgap Measure,’ US FDA’s Marks Says" - Pink Sheet, 6 Apr, 2022.)