Novavax COVID Vaccine Efficacy In Omicron, Delta Variants Among Unknowns Ahead Of Advisory Cmte
Executive Summary
US FDA also says there appears to be 'causal association' of myocarditis with the vaccine, which Novavax denies.
Novavax, Inc.’s proposed COVID-19 vaccine showed strong efficacy against older variants, but the US Food and Drug Administration now wonders how it will perform against the current virus strain.
The company is seeking an emergency use authorization for a two-dose primary series of its adjuvanted recombinant spike protein nanoparticle vaccine in adults 18 and older.
Novavax collected efficacy data for the vaccine from 27 December 2020 to 27 September 2021, when the Alpha variant was the dominant COVID-19 strain and before the Delta and Omicron variants emerged. None of the variants found in the study are considered variants of interest or variants of concern.
In briefing documents released ahead of a 7 June Vaccines and Related Biological Products Advisory Committee meeting on authorizing the vaccine for use, the FDA wrote that the Novavax study “analysis is less relevant to the current epidemiology of SARS-CoV-2.”
However, the agency still believes the vaccine will have some, although likely less, efficacy against current COVID-19 strains compared to earlier variants.
“Post-authorization experience with other COVID-19 vaccines has demonstrated substantially decreased effectiveness of a primary series against the currently circulating Omicron variant and sublineages, in particular against milder COIVD-19, than was demonstrated in pre-authorization clinical trials conducted when the ancestral strain was circulating,” the agency wrote in the briefing documents.
“Based on the efficacy estimate in the clinical trial of this vaccine, it is more likely than not that the vaccine will provide some meaningful level of protection against COVID-19 due to Omicron, in particular against more severe disease.”
VRBPAC members may discuss the issue during the meeting, which will be conducted virtually. A US Centers for Disease Control and Prevention official will give a presentation on the current epidemiology of COVID-19 and COVID-19 vaccination rates, according to the agenda.
The committee also will vote on whether the benefits of the vaccine outweigh the risks.
The question of efficacy amid current variants is a new one for the agency while considering an initial vaccine EUA. The agency decided to make the three other vaccines available well before the Delta and Omicron waves emerged.
Moderna, Inc.’s submission for full approval of its Spikevax COVID-19 vaccine was submitted during the Delta wave. And while the FDA review was ongoing, the Omicron wave began, which raised questions about the vaccine’s efficacy against that variant. Agency reviewers used limited laboratory data and published observational studies to assume that Spikevax’s efficacy would be lower against Omicron, compared to the original virus or Delta, but still concluded that the benefits-outweighed the risks. (Also see "COVID-19 Vaccines: Spikevax Review Reflected Changing Realities Of Omicron In US" - Pink Sheet, 3 May, 2022.)
Efficacy Lower In Some Subgroups
For the Novavax vaccine, overall efficacy seven days after the second dose in the pivotal study was 90.41%, and 91.06% among those age 18 to less than 65.
However, efficacy in adults 65 and older was only 78.63% with wide confidence intervals. The FDA wrote in the briefing that the limited number of cases in the subgroup, six, precluded a conclusion and requested a post-hoc analysis of efficacy among participants aged 50 to 64, along with a comparison of neutralizing antibody titers among those 50 to 64 with those age 65 and older.
The efficacy estimate for the age 50-64 group was 90.7%, which was comparable to the figure for the overall population. The immunogenicity comparison showed slightly lower neutralizing antibody titers in the age 65 and older group than the age 50-64 group, but the geometric mean titer ratio of 0.91 and lower bound of the 95% confidence interval would have met success criteria for immunobridging non-inferiority, the FDA wrote.
Efficacy among Hispanic or Latinos also was lower than most other subgroups. More cases appeared among Hispanics and Latinos in the vaccine group, nine, than the non-Hispanic or Latino group, eight.
Efficacy for Hispanics was pegged at 76.96% versus 94.22% for non-Hispanics. Efficacy among Whites (90.36%) Black or African Americans (93.93%) American Indian or Alaska Natives (91.88%) and Asians (100%) were comparable to the overall efficacy figure.
FDA, Novavax Dispute Myocarditis Findings
Novavax also likely will face questions about cases of myocarditis that the FDA believes may be associated with the vaccine but the company disputes.
Myocarditis was seen across the development program. The FDA wrote in the briefing documents that the cases “raise the concern for a causal association with this vaccine, similar to the association documented with mRNA COVID-19 vaccines.”
“Data from passive surveillance during post-authorization use in other countries also indicate a higher than expected rate of myocarditis and pericarditis,” the agency wrote. “However, interpretation of these passive surveillance data is not straightforward, and further evaluation is needed to inform the risk of myocarditis and pericarditis associated with this vaccine.”
Five events were reported within two weeks of vaccination, but only one had a clear alternative cause. The FDA also said in the documents that four events occurred in young men, a subpopulation known to be at higher risk of myocarditis with the mRNA vaccines (Pfizer Inc./BioNTech SE’s Comirnaty and Moderna’s Spikevax).
The agency also said that finding multiple cases in a premarket safety database “raises concern that if causally associated, the risk of myocarditis following [vaccination] could be higher than reported during post-authorization use of mRNA COVID-19 vaccines.”
A CDC official also is scheduled to give a presentation on COVID-19 vaccine-associated myocarditis during the VRBPAC meeting.
Novavax issued a statement 3 June denying myocarditis was associated with its vaccine.
“We have learned that we can expect to see natural background events of myocarditis in any sufficiently large database, and that young males are at higher risk,” the company said.
Novavax added that it calculated the myocarditis rate at 0.007% in the vaccine arm and 0.005% in the placebo arm of its studies, adding that it believed “there is insufficient evidence to establish a causal relationship.”
No myocarditis cases were found among mRNA vaccine recipients prior to authorization. But the issue became a large concern when cases began emerging. (Also see "mRNA COVID Vaccine Dosing Intervals May Be Extended To Mitigate Myocarditis Risk" - Pink Sheet, 4 Feb, 2022.)
A case of Guillain-Barre syndrome also was seen in the Novavax clinical trial “in temporal association post-vaccination and without an identified alternative cause,” the agency wrote.
In addition, the FDA said in the documents that active and passive surveillance post-authorization would further evaluate the risks of biliary, neurovascular, and cardiac events, as well as uveitis. The adverse events were infrequent in the clinical trials, but imbalances were seen in the vaccine group, compared to the placebo group.
Novavax could become the first protein-based COVID-19 vaccine to become available in the US. Even though the company received support from the Trump Administration’s Operation Warp Speed, the EUA submission was delayed. The agency received it on 1 February, and the path to advisory committee review has been unusually slow.
The vaccine already has received a conditional marketing authorization from the European Commission, emergency use listing from the World Health Organization, and emergency authorization in India, Indonesia and the Philippines. (Also see "Novavax Readies COVID-19 Vaccine Request For EUA, But How Much Longer Will The Door Be Open?" - Pink Sheet, 6 Jan, 2022.)