Novavax COVID-19 vaccine 90% efficacious in phase 3, but protection plummets against one variant

Novavax vaccine
Novavax is talking to the FDA but is yet to say when it will seek approval. (Novavax)

Novavax’s COVID-19 vaccine has achieved 89.3% efficacy in a phase 3 clinical trial that enrolled subjects exposed to the B.1.1.7 variant found in the U.K. However, the vaccine performed far worse in a smaller phase 2b that pitted it against another variant first identified in South Africa, intensifying concerns that updated prophylactics will be needed to protect against the evolving virus.

Clinical trials run by Pfizer, Moderna and the University of Oxford wrapped up before the emerging B.1.1.7 and B.1.351 variants began to account for a significant proportion of COVID-19 cases in any of the countries where subjects were enrolled. Moderna recently presented in vitro data suggesting its  vaccine is as effective against B.1.1.7 as prior variants but suffers a sixfold reduction in neutralizing titers with B.1.351. 

The Novavax clinical trials represent the first major controlled clinical tests of how a COVID-19 vaccine performs against the B.1.1.7 and B.1.351 variants. Overall, the results suggest Novavax’s vaccine may be as effective as any prophylactic studied to date against older variants.

In the 15,000-subject U.K. phase 3 clinical trial, Novavax saw 56 cases of COVID-19 in the placebo arm and six cases in the NVX-CoV2373 group at the interim analysis, resulting in an overall efficacy of 89.3%. All the cases in the vaccine cohort were mild or moderate. Twenty-seven percent of subjects were aged over 65 years. 

Novavax said 32 of the COVID-19 cases were infected with the B.1.1.7 variant. A post hoc analysis put the efficacy against B.1.1.7 at 85.6%, compared to an efficacy of 95.6% versus older variants. The efficacy of other vaccines against B.1.1.7 is unclear, because the phase 3 trials largely enrolled people at times and in places where the variant was yet to arrive and become predominant. 

Based on the available data, Novavax looks well set to successfully conclude the rolling submission it filed with the Medicines and Healthcare products Regulatory Agency earlier this month and go on to start shipping the 60 million doses bought by the U.K. government. The final analysis of the U.K. trial is still a few weeks away, and Novavax then expects to need another few weeks to prepare a filing. 

The major gap in the data made available so far relates to safety, with Novavax only stating “severe, serious and medically attended adverse events occurred at low levels and were balanced between vaccine and placebo groups.”

NVX-CoV2373 performed worse against B.1.351, potentially because all vaccines based on the virus identified in China early last year will struggle against the variant. In the 4,400-subject South African phase 2b, NVX-CoV2373 achieved efficacy of 49.4%. That population included HIV-positive subjects. In the subset of HIV-negative participants, efficacy was 60%.

Novavax has preliminary sequencing data on 27 of the 44 COVID-19 cases seen as of the cutoff. The analysis showed 92.6% of the cases involved infection with B.1.351.

One-third of the subjects were seropositive at baseline, indicating they had previously been infected with SARS-CoV-2. Novavax thinks most of those people were infected with the original COVID-19 strain. Based on that evidence, Novavax said the data suggest “prior infection with COVID-19 may not completely protect against subsequent infection” with B.1.351, but “vaccination with NVX-CoV2373 provided significant protection.”

It is possible factors other than B.1.351 contributed to the lower efficacy seen in South Africa. The phase 2b was relatively small, and other differences between the studies—such as their definitions of symptomatic disease—may have played a role. 

Yet, the clinical data still add to a growing body of evidence that existing COVID-19 vaccines may be less effective against B.1.351. Vaccine developers are acting accordingly. Novavax began working on new constructs against emerging strains early this month. Moderna is taking a version of its vaccine designed to protect against B.1.351 into preclinical studies and phase 1.  

Novavax thinks its approach, which entails delivering adjuvanted fragments of the spike protein made in insect cells, is well suited to the evolving situation. “A primary benefit of our adjuvanted platform is that it uses a very small amount of antigen, enabling the rapid creation and large-scale production of combination vaccine candidates that could potentially address multiple circulating strains of COVID-19,” Gregory Glenn, M.D., president of R&D at Novavax, said in a statement.

Enrollment in a phase 3 clinical trial of NVX-CoV2373 in the U.S. and Mexico is ongoing. Novavax has randomized more than 16,000 subjects so far, putting it more than halfway to its 30,000 target. The company is talking to the FDA but is yet to say whether it will be possible to seek approval before the U.S.-Mexico trial is complete. Novavax expects the U.K. to be the first country to approve the vaccine.