Interim Recommendation of the Advisory Committee on…

Summary of Evidence for Use of the Novavax COVID-19 Vaccine in Persons Aged ≥18 Years

The body of evidence regarding efficacy of the Novavax COVID-19 vaccine among persons aged ≥18 years consisted of data from one randomized, double-blind, placebo-controlled phase III clinical trial (2019nCoV-301), based in the United States and Mexico, in which 29,945 participants aged ≥18 years were enrolled and randomized 2:1 to receive 2 intramuscular doses of either Novavax COVID-19 vaccine (5 μg rS and 50 μg Matrix-M adjuvant) or saline placebo, separated by an interval of 3 weeks (3). Upon completion of the assigned study arm (i.e., receipt of either 2 doses of vaccine or 2 doses of placebo), trial participants were offered the opportunity to cross over in a blinded fashion (“blinded crossover”) from their originally assigned study arm. Therefore, all trial participants had the opportunity to receive trial vaccine in either the precrossover or postcrossover period, while remaining blinded throughout. Efficacy and safety data are available from the precrossover period (December 27, 2020–September 27, 2021) of this trial, and these data comprise the basis of the assessment made using the GRADE approach. Data from additional sources were considered in assessment of benefits and harms, as guided by the EtR Framework. These sources included additional safety data available from the postcrossover period of 2019nCoV-301, safety data from three additional Novavax clinical trials based in the United Kingdom (2019nCoV-302), South Africa (2019nCoV-501), and Australia (2019nCoV-101), postmarketing safety data submitted to FDA by Novavax summarizing administration of 744,235 doses of Novavax COVID-19 vaccine globally as of April 30, 2022 (4), and publicly available data pertaining to the administration of 160,000 Novavax COVID-19 vaccine doses in Australia as of June 26, 2022 (5).

The primary efficacy endpoint was diagnosis of RT-PCR–confirmed symptomatic COVID-19 ≥7 days after receipt of the second dose in the 2-dose primary series of Novavax COVID-19 vaccine arm compared with that in the placebo arm. Per the manufacturer’s trial protocol, COVID-19 cases were only included in the efficacy analysis if they were RT-PCR–confirmed by a designated central laboratory. The primary efficacy endpoint was assessed until a participant received the first blinded crossover vaccination or until the data cutoff date of September 27, 2021, whichever occurred earlier. The per-protocol VE analysis population included 17,272 Novavax COVID-19 vaccine recipients and 8,385 placebo recipients with a median 2.5 months of blinded follow-up after receipt of dose 2. VE^§§ against RT-PCR–confirmed symptomatic COVID-19, observed during the period of Alpha variant predominance, was 89.6% (95% CI = 82.4%–93.8%) in persons aged ≥18 years without evidence of previous SARS-CoV-2 infection.^¶¶ This estimate was based on symptomatic illness in 17 vaccine recipients and 79 placebo recipients, none of whom was hospitalized. VE against severe COVID-19*** was 100%, based on four severe cases in the placebo group and none in the vaccine group. Subgroup analyses by age demonstrated VE against RT-PCR–confirmed symptomatic COVID-19 of 90.3% (95% CI = 83.1%–94.4%) among participants aged 18–64 years and 76.3% (95% CI = 29.1%–95.7%) among participants aged ≥65 years. A post hoc analysis of VE^††† among participants aged 50–64 years demonstrated VE of 90.7% (95% CI = 72.9%–96.8%) against RT-PCR–confirmed symptomatic COVID-19. Additional evidence pertaining to potential VE in persons aged ≥65 years was provided through immunobridging. The measure of immune response to 2 doses of Novavax COVID-19 vaccine in persons aged ≥65 years without evidence of previous SARS-CoV-2 infection was slightly lower than that observed in persons aged 50–64 years, with a geometric mean ratio (GMR) for day 35 neutralizing antibody titer of 0.91 (95% CI = 0.68–1.2) for persons aged ≥65 years, demonstrating estimates that would have met FDA’s usual success criterion for immunobridging noninferiority.^§§§ Subgroup analyses of VE against RT-PCR–confirmed symptomatic COVID-19 by ethnicity and race demonstrated that most estimates by ethnicity and race (when calculable from the data) were comparable to the per-protocol VE overall, but VE in participants of Hispanic or Latino (Hispanic) ethnicity was lower (75.7%; 95% CI = 46.0%–89.1%).

Among vaccine recipients aged ≥18 years, reactogenicity, defined as solicited local and systemic reactions during the 7 days after vaccination, was reported frequently. Following dose 2, 78.6% of participants reported any local reactions, and 69.3% reported any systemic reactions. Most solicited reactions were mild to moderate and lasted 1–3 days; all were reported more frequently after dose 2 than after dose 1 among vaccine recipients. Severe solicited reactions (grade 3 or higher, defined as interfering with daily activity) were more common in vaccine (16.3%) than placebo (4.0%) recipients. Severe solicited local reactions occurred in 1.1% of vaccine recipients after dose 1 and in 6.7% after dose 2, compared with 0.2% and 0.3%, respectively, in placebo recipients. Severe solicited systemic reactions occurred in 2.4% of vaccine recipients after dose 1 and in 12.1% after dose 2, compared with 2.1% after each dose among placebo recipients. Reported reactions varied with age and were more common among vaccine recipients aged 18–64 years than among those aged ≥65 years. Among vaccine recipients aged 18–64 years, the most common reactions associated with any vaccine dose included injection site pain or tenderness (82.2%), fatigue (62.0%), muscle pain (54.1%), and headache (52.9%). In participants aged ≥65 years, the most common vaccine-associated reactions associated with any dose included injection site pain or tenderness (63.4%), fatigue (39.2%), muscle pain (30.2%), and headache (29.2%). The most common grade 3 or higher local reaction reported by vaccine recipients after dose 2 was pain or tenderness at the injection site (6.3%). The most common grade 3 or higher systemic reaction reported by vaccine recipients after dose 2 was fatigue (10.5%). Reports of unsolicited serious adverse events^¶¶¶ were comparable between vaccine (1.0%) and placebo (1.1%) recipients in the precrossover period and among participants who crossed over to receive Novavax COVID-19 vaccine (1.4%) and placebo (1.2%) in the postcrossover period.

Cases of myocarditis or pericarditis were detected in Novavax clinical trials. Among a total of 41,546 vaccine recipients aged ≥16 years, including within both precrossover and postcrossover vaccine arms in 2019nCoV-301, as well as all vaccine recipients in 2019nCoV-302, 2019nCoV-501, and 2019-nCoV101 combined, six cases of myocarditis or pericarditis were detected; five occurred within 20 days of vaccination. Among these five, four did not have likely alternative etiologies, suggesting a possible causal relationship with vaccine. Cases of myocarditis or pericarditis have also been detected in global postauthorization surveillance; during a period in which 744,235 doses of Novavax COVID-19 vaccine were administered in Australia, Canada, the European Union, New Zealand, and South Korea, 35 reports (representing 36 adverse events) were identified among 20 male and 15 female vaccine recipients with a median age of 34 years (range = 23–62 years): 29 reports of pericarditis, including five in persons with a history of pericarditis after mRNA COVID-19 vaccine; four myocarditis cases; two myopericarditis cases; and one case of carditis, not otherwise specified. A postmarketing analysis from Australia identified three cases of myocarditis and 12 cases of pericarditis reported during a period in which 160,000 Novavax COVID-19 vaccine doses were administered (5).

In addition to the myocarditis or pericarditis cases detected in Novavax clinical trials, one case of angioedema (2019nCoV-301) and one case of Guillain-Barré syndrome (2019nCoV-302) were also considered to be potentially related to vaccination. A detailed summary of safety data, including information on reactogenicity, is available at https://www.cdc.gov/vaccines/covid-19/info-by-product/novavax/reactogenicity.html.

From GRADE evidence assessment, the level of certainty for the benefits of Novavax COVID-19 vaccination among persons aged ≥18 years was type 1 (high certainty) for the prevention of symptomatic laboratory-confirmed COVID-19 assessed using direct efficacy. Evidence was type 3 (low certainty) for prevention of COVID-19–associated hospitalization. No COVID-19–associated hospitalizations were present in the per-protocol trial efficacy analysis; therefore, the outcome was evaluated using severe COVID-19 as a surrogate measure. Concerns of imprecision arose because of the small number of severe COVID-19 events. Regarding potential harms after vaccination, evidence was type 1 (high certainty) for serious adverse events and reactogenicity of grade 3 or higher. No data were available to assess other GRADE benefits, including prevention of death due to COVID-19 or prevention of asymptomatic SARS-CoV-2 infection.