New England Journal of Medicine February 10, 2022

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico

Lisa M. Dunkle, Karen L. Kotloff, Cynthia L. Gay, Germán Áñez, Jeffrey M. Adelglass et al.

Bottom Line

The PREVENT-19 Phase 3 trial demonstrated that the protein subunit vaccine NVX-CoV2373 has a 90.4% overall efficacy against symptomatic COVID-19 and 100% efficacy against moderate-to-severe disease in adults, with a reassuring safety profile.

Key Findings

1. The NVX-CoV2373 vaccine demonstrated 90.4% (95% CI, 82.9 to 94.6) overall vaccine efficacy against symptomatic COVID-19, with 14 cases among vaccine recipients compared to 63 among placebo recipients over a 3-month period.

2. Vaccine efficacy against moderate-to-severe COVID-19 was 100% (95% CI, 87.0 to 100), as all 14 moderate-to-severe cases occurred in the placebo group.

3. Vaccine efficacy among high-risk individuals (those ≥65 years, with comorbidities, or frequent exposure) was 91.0% (95% CI, 83.6 to 95.0).

4. The vaccine was highly protective during a period of variant emergence, demonstrating 92.6% (95% CI, 83.6 to 96.7) efficacy against variants of concern or interest, which were predominantly the Alpha variant during the study period.

5. Adverse events were mostly mild-to-moderate and transient, with local injection-site tenderness, fatigue, headache, and muscle pain occurring more frequently in the vaccine group than placebo, particularly after the second dose.

Study Design

Design

Phase 3 RCT

Observer-Blinded

Sample

29,949

Patients

Duration

3 months

Median

Setting

US and Mexico

Population Adults 18 years of age and older who were healthy or had stable chronic medical conditions, including those at high risk for acquiring severe SARS-CoV-2 infection.

Intervention Two 5-μg doses of NVX-CoV2373 (recombinant nanoparticle spike protein) with 50-μg Matrix-M adjuvant administered intramuscularly 21 days apart.

Comparator Saline placebo administered intramuscularly 21 days apart.

Outcome First occurrence of virologically confirmed symptomatic mild, moderate, or severe COVID-19 with onset at least 7 days after the second injection in baseline seronegative participants.

Study Limitations

• The primary efficacy analysis was conducted before the widespread circulation of the Delta and Omicron variants, limiting the assessment of efficacy against later strains.

• The median follow-up of approximately 3 months limits the assessment of the long-term duration of protection and rare adverse events (such as myocarditis or pericarditis).

• Certain vulnerable groups, such as pregnant women and severely immunocompromised individuals, were not extensively represented in the primary trial cohort.

• The subsequent unblinding and crossover of placebo participants limited the ability to collect long-term placebo-controlled safety data.

Clinical Significance

NVX-CoV2373 provides a highly effective, traditional protein-subunit alternative to mRNA and viral vector vaccines. Its conventional refrigeration requirements (2°C to 8°C) make it uniquely suited for global distribution in resource-limited settings, and it offers an important option for individuals hesitant about or contraindicated for newer vaccine platforms.

Historical Context

Developed during the COVID-19 pandemic as part of 'Operation Warp Speed', Novavax's NVX-CoV2373 was an adjuvanted, recombinant spike protein nanoparticle vaccine (utilizing the Matrix-M adjuvant). While it arrived later than the mRNA (Pfizer/Moderna) and adenovirus (J&J/AstraZeneca) vaccines, it provided a more traditional vaccine technology (protein subunit) that played a critical role in expanding the global vaccine portfolio and mitigating vaccine hesitancy related to newer technologies.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of NVX-CoV2373, a protein subunit vaccine with a Matrix-M adjuvant, differ fundamentally from the mRNA COVID-19 vaccines, and what specific role does the adjuvant play in generating immunity?

Key Response

This question addresses foundational immunology. NVX-CoV2373 delivers a pre-formed recombinant full-length spike protein directly to the body, whereas mRNA vaccines deliver genetic instructions for host cells to synthesize the protein endogenously. The saponin-based Matrix-M adjuvant is crucial because purified proteins alone are poorly immunogenic; it acts to stimulate innate immunity, recruit antigen-presenting cells to the injection site, and enhance both cellular (Th1) and humoral immune responses.

Resident

A 35-year-old patient who previously refused mRNA vaccines due to concerns about new genetic technology and myocarditis asks about the Novavax vaccine. Based on the PREVENT-19 trial, how would you counsel them regarding its efficacy and safety profile compared to mRNA options?

Key Response

This focuses on clinical application and addressing vaccine hesitancy. The resident should highlight the 90.4% overall efficacy and 100% efficacy against moderate-to-severe disease demonstrated in the trial. They can reassure the patient that it utilizes a traditional protein subunit platform, similar to Hepatitis B or acellular pertussis vaccines, which may alleviate concerns about novel platforms, while noting the reassuring safety profile seen in the trial with primarily mild, transient local reactogenicity.

Fellow

The PREVENT-19 trial was conducted predominantly when the Alpha variant was circulating, prior to the major Delta and Omicron waves. Immunologically, how might the choice of the ancestral strain spike protein in NVX-CoV2373 affect its neutralizing capacity against emerging immune-evasive variants, and what mechanisms maintain its strong protection against severe disease?

Key Response

This requires advanced understanding of viral evasion. Fellows should recognize that while neutralizing antibodies against the receptor-binding domain (RBD) wane or are evaded by heavily mutated variants like Omicron, the full-length spike protein presentation in combination with the potent adjuvant preserves diverse T-cell epitopes and non-neutralizing binding antibodies (e.g., mediating antibody-dependent cellular cytotoxicity), which continue to offer robust protection against moderate-to-severe clinical outcomes.

Attending

Given the near-ubiquity of prior SARS-CoV-2 infection or vaccination in current practice, how might the integration of a protein subunit vaccine like NVX-CoV2373 into our booster armamentarium alter the phenomenon of immunological imprinting (original antigenic sin), and what is the clinical advantage of heterologous boosting?

Key Response

This explores high-level public health strategy and advanced immunology. Attendings should discuss whether switching vaccine platforms (e.g., from mRNA to a protein subunit) might broaden epitope recognition or alter the breadth of the memory B-cell repertoire compared to homologous mRNA boosting, offering a theoretical advantage in generating more cross-reactive immunity against future variants.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PREVENT-19 trial eventually utilized a blinded crossover design where placebo recipients were offered the active vaccine. How does this unblinding and crossover impact the long-term assessment of vaccine durability and the detection of delayed rare adverse events, and what statistical methodologies can be employed to mitigate the loss of a concurrent control arm?

Key Response

This focuses on clinical trial methodology and its trade-offs. While ethically necessary during a pandemic, crossover designs eliminate the concurrent placebo group for long-term follow-up. PhDs should discuss advanced statistical techniques, such as marginal structural models or inverse probability weighting, to estimate long-term efficacy and acknowledge the inherent limitations in assessing rare safety signals without a true long-term control.

Journal Editor

As a peer reviewer for this trial, what concerns would you raise regarding the changing epidemiological landscape and varying local attack rates during staggered enrollment across the US and Mexico, and how might these factors introduce period-by-treatment interactions that skew the overall efficacy estimates?

Key Response

This evaluates trial context and methodological rigor. Efficacy is highly dependent on the specific variants circulating and local transmission dynamics. If one study arm or demographic subgroup is exposed to a higher viral load or a new immune-evading variant due to staggered geographical enrollment, it can confound the data. A critical reviewer would look for robust stratified analyses adjusting for site and time-varying incidence.

Guideline Committee

In light of the PREVENT-19 data demonstrating high efficacy and safety, how should national immunization advisory committees (such as the ACIP) position NVX-CoV2373 relative to mRNA vaccines in their guidelines, specifically considering whether it should be recommended as an equal alternative, a preferred option for specific populations, or reserved for those with mRNA contraindications?

Key Response

This translates trial evidence into policy. The committee must weigh the 90.4% efficacy and favorable reactogenicity profile against the massive volume of real-world effectiveness and safety data already accumulated for mRNA vaccines. Current guidelines often position Novavax as a crucial alternative for individuals unable or unwilling to receive mRNA vaccines, and this question asks how the trial data justifies or challenges that specific tiering of recommendations.

Clinical Landscape

Noteworthy Related Trials

2020

BNT162b2 Phase 3 Efficacy Trial

n = 43,548 · NEJM

Tested

BNT162b2 mRNA vaccine

Population

Adults and adolescents at risk of COVID-19

Comparator

Placebo

Endpoint

Symptomatic COVID-19 at least 7 days post-dose 2

Key result: The vaccine demonstrated 95% efficacy against COVID-19 and had a favorable safety profile.

2021

COVE Trial

n = 30,420 · NEJM

Tested

mRNA-1273 vaccine

Population

Adults at high risk for COVID-19 infection or severe disease

Comparator

Placebo

Endpoint

First occurrence of symptomatic COVID-19 at least 14 days post-dose 2

Key result: Demonstrated 94.1% efficacy in preventing COVID-19 illness, including severe disease.

2021

ENSEMBLE Trial

n = 43,783 · NEJM

Tested

Ad26.COV2.S viral vector vaccine

Population

Adults 18 years and older

Comparator

Placebo

Endpoint

Moderate to severe-critical COVID-19 at least 14 and 28 days post-vaccination

Key result: A single dose was 66.9% effective against moderate to severe-critical COVID-19 with high protection against hospitalization and death.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis