FDA tiptoes around issue of COVID-19 boosters ahead of AdCom

In documents posted to the FDA's website on Wednesday ahead of an advisory committee (AdCom) meeting this week, agency reviewers declined to take a firm stance on whether or not to back booster doses of Pfizer and BioNTech's COVID-19 vaccine Comirnaty, saying the regulator had not reviewed all the available data yet. However, they noted that "overall, data indicate that currently US-licensed or authorised COVID-19 vaccines still afford protection against severe…disease and death."

The Biden administration has said it wants to begin offering boosters to most vaccinated Americans as early as next week, pending authorisation from the FDA, based on data showing waning immunity over time and weaker protection against the Delta variant. The AdCom scheduled for this Friday will take place days after a group of US and international scientists, including Marion Gruber, director of the FDA's Office of Vaccines Research and Review (OVRR), and Philip Krause, deputy director of the FDA's Center for Biologics Evaluation and Research, wrote in The Lancet that there is currently insufficient evidence available to warrant boosting the general population.

In the FDA briefing documents released Wednesday, agency staff said "there are many potentially relevant studies, but FDA has not independently reviewed or verified the underlying data or their conclusions." The FDA reviewers noted that while some observational studies suggest Comirnaty's efficacy dwindles over time against symptomatic infections or against the Delta variant, others have not. They also cautioned about "known and unknown biases [in observational studies] that can affect their reliability."

Pfizer, BioNTech make their case

For their part, Pfizer and BioNTech argue that "the totality of the available data supports the public health need" for a third dose of Comirnaty, to be given about six months after the second dose in people 16 years and older. In their AdCom briefing documents, the companies highlighted recent data from Israel and the US covering a period during which Delta was the predominant strain, and which showed vaccine protection wanes approximately six to eight months following the second dose.

Specifically, they cited a recent real-world, retrospective study conducted in Israel that looked at data from June and July. The study found that individuals vaccinated in January had a significant 2.26-fold higher risk of breakthrough infections compared to those vaccinated in April. They also pointed to an observational study done by the Israeli health ministry showing that the effectiveness of Comirnaty against SARS‑CoV-2 infection fell to 39% in June and July, compared with efficacy of over 95% earlier this year in a period from January to April.

Waning immunity vs. Delta

Another recent study conducted at the Kaiser Permanente Southern California health system in the US evaluated real-world effectiveness of Comirnaty against infections and hospitalisations by time since vaccination. According to Pfizer and BioNTech, results here showed that, at least four months after full vaccination, Comirnaty's efficacy against Delta infections declined to 53%, although it was 93% effective at preventing Delta-related hospitalisations. The companies noted that the variant-specific analysis done by Kaiser suggest reductions in vaccine efficacy "are likely primarily due to waning effectiveness rather than Delta escaping vaccine protection." They pointed to the fact that potency against Delta infections was over 90% early on, and that the reduced efficacy was seen regardless of the variant.

Pfizer and BioNTech also disclosed data from a post-hoc analysis of the pivotal Phase III study that was used to authorise Comirnaty, previously known as BNT162b2, in the first place back in December. They said results showed that the incidence of breakthrough cases was higher among people who received their second dose at the end of last year, compared to those who received it after March 2021.

No new adverse reactions

Regarding safety, Pfizer and BioNTech said side-effects from a Comirnaty booster are similar to those felt after the second dose and are more likely to affect younger people. The majority of side effects to the booster were mild or moderate in severity, and there were no new adverse reactions, they added.

Specifically, data from about 300 participants ages 18 to 55 in the Phase III trial showed that 63.7% experienced fatigue after getting their third dose of Comirnaty, while 48.4% had headaches and 39.1% felt muscle pain. The companies said 44 recipients developed at least one unexpected adverse event within one month after getting the booster shot, with lymphadenopathy being the most common. There were no reported cases of anaphylaxis, hypersensitivity, Bell's palsy, appendicitis, myocarditis or pericarditis among participants, the companies said.

Moderna chimes in with new data

Separately, Moderna released a new analysis from the Phase III COVE study used to back the efficacy of its COVID-19 vaccine mRNA-1273, saying the data point to declining efficacy over time. The company is also seeking an FDA nod for a booster dose of its vaccine.

The new analysis compared COVE participants randomised to mRNA-1273 against those who were initially in the study's placebo arm, but who then crossed over to receive the vaccine. Specifically, it looked at breakthrough infections in July and August, by which point people in the initial vaccinated group had received their first dose of mRNA-1273 a median 13 months earlier, whereas only about eight months had elapsed since the cross-over group got their first dose.

Moderna said there were 49 breakthrough cases of COVID-19 per 1000 person-years in those who were vaccinated more recently, versus 77 cases per 1000 in the group vaccinated last year, translating to 36% reduction in incidence.

However, the company also pointed to real-world analysis of its vaccine done by Kaiser Permanente Southern California, with follow-up through June 30, during the emergence of the Delta variant. The strain was identified in 47% of cases in fully vaccinated individuals, Moderna said. Results showed that two doses of mRNA-1273 was 87% protective against COVID-19 diagnosis and 96% effective against hospitalisations. Still, Moderna stated that it "believes data support benefit of an mRNA-1273 booster dose."

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