After a long delay marred by manufacturing troubles, a COVID-19 vaccine from the small Maryland-based biotech company Novavax became the fourth such vaccine authorized in the U.S. Here, we review how it works and how it’s different from its competitors.
Vaccine name: NVX-CoV2373
Design type: Adjuvanted protein subunit
Dose number: 2, three to eight weeks apart
Efficacy: 90.4% efficacy in preventing symptomatic COVID-19 in people 18 years of age or older a week or more after the second dose, as measured in a clinical trial prior to the emergence of the omicron variant.
Safety: Trial data indicate the shots increase the rare risk of myocarditis and pericarditis, or inflammation of the heart muscle and the tissue surrounding the heart.
Doses administered: As of Aug. 10, more than 9,700 doses have been administered in the U.S. For the latest vaccination information, see the Centers for Disease Control and Prevention’s COVID Data Tracker.
Operation Warp Speed involvement: Novavax received $1.75 billion from the U.S. government as part of OWS to support development, manufacturing and to buy 100 million doses (3.2 million were secured as of FDA authorization).
Storage considerations: Standard refrigerator temperatures for up to nine months.
The Novavax vaccine is the fourth COVID-19 vaccine authorized for use in the U.S. and the first to use a protein-based approach commonly used in other vaccines.
Officials hope that the traditional vaccine design is attractive to those who have been wary of the newer mRNA technology. The shot may also be particularly useful in vaccinating individuals with known allergies to the mRNA vaccines.
Results from phase 3 randomized controlled trials testing the Novavax COVID-19 vaccine in adults were announced in June 2021 and published in the New England Journal of Medicine in December. The company, however, did not submit its request for emergency use authorization to the Food and Drug Administration until Jan. 31, in part due to manufacturing issues.
In a 21 to 0 vote, with one abstention, an outside panel of experts advising the FDA recommended authorizing the Novavax vaccine on June 7. More than a month later, after review of additional manufacturing data, the FDA agreed that the known and potential benefits outweigh the known and potential risks and issued an EUA.
On July 19, the vaccine committee advising the CDC also recommended the vaccine in a 12 to 0 vote, and the agency signed off on the shot — more than a year and a half after doing so for the Pfizer/BioNTech and Moderna vaccines.
Currently, the Novavax vaccine is not available as a booster, although the company has collected trial data on boosters and a booster dose has been authorized in Australia.
Some data, presented to the FDA advisory committee in late June, suggest a third Novavax dose may be particularly good at eliciting a broad immune response — and could provide as good protection against omicron as two doses fared against the first coronavirus variants.
In May, Novavax announced it was starting a phase 3 trial of an omicron-specific vaccine as a booster.
Novavax announced in August that it started a pediatric trial of its vaccine in children 6 months to 11 years of age, which will begin with evaluations in 6- to 11-year-olds. Results are not expected until 2023.
What is in the vaccine and how does it work?
As with other COVID-19 vaccines, the Novavax vaccine works by triggering an immune response against the spike protein of the SARS-CoV-2 virus, which sits on the surface of the virus and is what the virus uses to enter cells.
Unlike the vaccines from Pfizer/BioNTech and Moderna, however, which instruct cells in the body to make the spike protein using mRNA “instructions,” the Novavax vaccine is more direct: the shot itself contains the spike proteins.
This is similar to the way many existing vaccines work, including the hepatitis B vaccine, which 30 years ago became the first protein subunit vaccine, along with vaccines that protect against influenza, HPV, and whooping cough, or pertussis.
Many proteins used in vaccines are so-called recombinant proteins, since they are made in large quantities in cultured cells, usually in yeast or bacteria. In Novavax’s case, though, the spike proteins are made in insect cells, specifically fall armyworm moth cells. (Not to worry, these cells are also grown in culture — no insects are reared for this purpose!)
Once the Novavax spike proteins are made and purified, they’re mixed with tiny synthetic nanoparticles. As many as 14 spike proteins will self-assemble around a nanoparticle core, creating spike-studded particles that mimic the structure of the coronavirus.
A plant-derived adjuvant is also added to the spike nanoparticles to augment the immune response, since the spike proteins alone do not generate a robust immune response.
Adjuvants are often needed with protein subunit vaccines because unlike vaccines that use weakened or killed germs, subunit vaccines contain only part of the pathogen. This makes the vaccines generally safer and with fewer side effects, but without an added component to stimulate the innate immune system, the vaccine isn’t able to provide good long-term immunity.
As with all other authorized or approved COVID-19 vaccines, there is no way to catch COVID-19 from the Novavax vaccine since it doesn’t contain any virus.
How is the Novavax vaccine different from its competitors?
As just discussed, the main difference between the Novavax vaccine and the mRNA COVID-19 vaccines is the more standard vaccine design. Protein subunit vaccines are common, and include hepatitis B and influenza vaccines, among others.
Even compared with the J&J vaccine, which uses a viral vector, the protein-based approach is more typical for vaccines. Prior to COVID-19, only a couple of viral vector vaccines were in use — for example, to protect against Ebola — although the technology had been studied for decades.
Novavax’s more traditional vaccine design may be able to win over some vaccine holdouts, but it remains to be seen how many people will get vaccinated now that Novavax is an option.
Because Novavax is made of different ingredients than the mRNA vaccines, some individuals with known allergies to those ingredients may be able to get the Novavax vaccine instead. The Novavax vaccine doesn’t contain polyethylene glycol, or PEG, for example, but does contain polysorbate, which is very similar to PEG. (Allergies to those ingredients have been suspected to be problematic in rare cases, but accumulating evidence suggests people with such allergies can be vaccinated without issue.)
Another advantage of the Novavax vaccine is that it can be stored for a long time at regular refrigerator temperatures, similar to most standard vaccines — but unlike the mRNA COVID-19 vaccines, which must be kept frozen or in ultracold freezers for long-term storage. This could make the Novavax vaccine more useful in harder-to-reach places that do not have access to such extreme temperature-controlled supply chains, or “cold chains.”
How was the vaccine developed?
Novavax was quick to begin working on a coronavirus vaccine, saying as early as Jan. 21, 2020 that it was developing a candidate vaccine. By February, the company, which had developed an experimental vaccine against SARS but had never produced a licenced product, said it was evaluating different candidates in animal models.
In May 2020, Novavax began a phase 1 clinical trial in about 130 adults, following a more than $380 million investment from the nonprofit Coalition for Epidemic Preparedness Innovations. The company also received support from the U.S. government, including $1.6 billion as part of Operation Warp Speed, and other money from the Department of Defense.
In August 2020, Novavax started a phase 2 trial in the U.S. and Australia and a phase 2b trial in South Africa. The following month, Novavax launched what would become a 15,000-person phase 3 trial in the U.K.
Due to difficulty manufacturing enough vaccines doses, the company did not begin its U.S- and Mexico-based phase 3 trial, which included about 30,000 participants, until late December 2020, after the Pfizer/BioNTech and Moderna vaccines had already received emergency authorization.
Because other vaccines became available during the course of the trial, participants had the option to “cross over” to the other treatment arm once they were eligible for vaccination. Participants were not told whether they received the vaccine or placebo for either of the shots.
How effective is the vaccine?
In its primary randomized controlled trial in the U.S. and Mexico, which was done prior to the omicron variant, the Novavax vaccine had a 90.4% efficacy in preventing symptomatic COVID-19 at least a week after the second dose. As we’ve explained before, this means the vaccine reduced the risk of developing symptomatic illness by more than 90%.
The trial included nearly 30,000 adults, two-thirds of whom received the vaccine, and one-third who served as controls. The 90.4% efficacy figure was based on 17 confirmed COVID-19 cases in the vaccinated group and 79 in the placebo group. All of the COVID-19 cases in the vaccinated group were mild; nine moderate and four severe cases occurred in the placebo group.
Vaccine efficacy was lower — at 78.6% — and more uncertain among participants 65 years of age and older, due to the low number of COVID-19 cases that accrued. Those older vaccine recipients, however, still had comparable neutralizing antibody responses to slightly younger participants, the FDA noted in its briefing document reviewing the data.
There were no differences by ethnicity and race except for Hispanic or Latino participants, who had a lower estimated efficacy of 77.0%. The company suspects that this finding was a fluke, or possibly due to “unidentified viral or host factors.” The CDC and others have said that the result doesn’t make much sense physiologically. Novavax said during the FDA committee’s meeting that Hispanic or Latino participants had slightly higher antibody responses to the vaccine than non-Hispanic participants and that it would continue to study the issue in its post-marketing effectiveness studies.
The trial was conducted primarily when the alpha variant was dominant, prior to both the delta and omicron variants. Against omicron, it’s likely the two-dose Novavax vaccine will still protect against more serious disease, even if protection against infection is low. The company has been studying booster doses, but will have to submit an application to the FDA before those up for agency authorization.
Novavax conducted several other late-phase trials, but the FDA only considered efficacy data from the American and Mexican trial. The agency said it “could not conclude” that the vaccine doses used in the other trials, which were made by another manufacturer, were “comparable.”
In one of the trials, a large phase 3 study in the U.K. conducted during the alpha era, the Novavax vaccine had an efficacy of 89.7% against symptomatic COVID-19 in adults up to the age of 84 after an average of three months after the second dose. Against the original version of the coronavirus, the vaccine had an even higher 96.4% efficacy.
After six months of follow-up, the efficacy against symptomatic disease in the U.K. study declined a bit to 82.7%. Efficacy against severe disease remained 100%.
In South Africa, in a smaller trial of around 4,400 people conducted when the beta variant was dominant, the Novavax vaccine was found to have an efficacy of 49.4% in preventing symptomatic disease, which rose to 60.1% when excluding individuals with HIV infection.
How safe is the vaccine?
The most common side effects reported in the trials were injection site pain, tiredness, headache, and muscle pain. According to the FDA’s briefing document, these types of side effects, which are expected after vaccination, typically lasted one to three days and were more common and more severe after the second dose relative to the first and among younger adults compared with older people.
The Novavax vaccine appears to be similar to or better than other COVID-19 vaccines with respect to these expected side effects, which aren’t typically dangerous, but have been more intense than those from most other vaccines.
Cases of myocarditis or pericarditis, inflammation of the heart muscle or its surrounding tissues, were reported in the clinical trials, with six cases among vaccine recipients (out of 41,546 people) and one case among the placebo group, according to the FDA.
Novavax has argued that in its trials, the health conditions occurred at roughly the same frequency prior to crossover and not above the expected rate following crossover, so there “is insufficient evidence to establish a causal relationship.”
The FDA has been more circumspect, noting that in four of the vaccine cases the timing and lack of other explanations “supports a concern for causal relationship” to the vaccine. In the four cases, the patients were hospitalized but fully recovered.
Data from other countries that have already authorized the Novavax vaccine also “indicate a higher-than-expected rate of myocarditis and pericarditis (mainly pericarditis) associated with the vaccine,” the FDA said, although the agency cautioned that further evaluation was needed.
Myocarditis and pericarditis have been identified as rare but serious side effects of mRNA vaccination, although no such cases occurred during the Pfizer or Moderna trials.
Some data with the mRNA vaccines have suggested that more time between doses can lower the risk of myocarditis or pericarditis. Although there is no specific data on that for the Novavax vaccine, the CDC’s vaccine advisory group concluded that instead of the tested three-week interval, an eight-week interval “may be selected to potentially reduce the risk for myocarditis or pericarditis after vaccination.”
The FDA decided to include myocarditis and pericarditis as a risk of the vaccine on its fact sheet, but said the likelihood of it occurring was “very low.”
One case of Guillain-Barré Syndrome, a disorder in which the immune system attacks nerve cells, was reported in a vaccine recipient in the trials, which the FDA considered to be vaccine-related.
In the trials, there were other small imbalances of some uncommon adverse events in the vaccine and placebo groups, including inflammation of the gallbladder (cholecystitis), inflammation of the eye (uveitis), and some cardiac and clotting events. According to the FDA, a causal relationship of these events to the vaccine “cannot be concluded based on available data.”
Editor’s note: This story will be updated as necessary.
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