Novavax Covid-19 vaccine booster: questions to answer
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Novavax Covid-19 vaccine booster: safety and manufacturing questions remain

By Reynald Castaneda 02 Sep 2021

Novavax’s Covid-19 vaccine could find its niche as a booster shot, but questions linger around its safety and production.

Novavax Covid-19 vaccine booster: safety and manufacturing questions remain
Novavax has delayed its US application several times due to manufacturing checks and its filing is now anticipated in Q4. Credit: rarrarorro / Shutterstock.com

Need to know:

  • Novavax’s vaccine is yet to be widely used anywhere; the US and Europe are powering through in their deployment of competitor COVID-19 vaccines. This means Novavax’s best bet for market uptake in these territories is via booster use.
  • Novavax would diversify vaccine options and potentially fill supply gaps.
    But the vaccine’s safety profile is yet to be fully understood compared to its competitors, which have now been used in millions of people. Also, manufacturing of protein subunit vaccines such as Novavax’s is much more complicated than mRNA vaccines.
  • On the positive side, switching to Novavax as a booster is unlikely to offer lower protection compared with people who stuck with the same vaccine technology.

Questions on Novavax’s Covid-19 vaccine as a booster remain, given the potential for rare side effects and the need for manufacturing agility. This is despite the company’s booster positioning being a sound market tactic in certain countries, experts said.

Granting Novavax’s vaccine, NVX-CoV2373, an emergency authorisation would increase options for boosters and fulfil possible shortages. But NVX-CoV2373 and its adjuvant are yet to be widely distributed anywhere and thus their safety profile has yet to be fully established. Also, protein subunit vaccines such as NVX-CoV2373 have time-consuming manufacturing protocols, and longer timelines should be expected, a vaccine manufacturing expert noted. A manufacturing step that can take days for an mRNA vaccine may take weeks with a protein subunit vaccine, he explained.

Novavax has delayed its US application several times due to manufacturing checks and its filing is now anticipated in Q4. Meanwhile, in Europe, NVX-CoV2373 is in a rolling review process. Once authorised in these territories, it may mainly be deployed as a booster – the third dose after a two-dose regimen. In interviews, Novavax CEO Stanley Erck has said the vaccine’s use as a booster might be its biggest market in the US.

Countries deep into booster plans

As a heterologous booster for use in fully vaccinated individuals, experts do not expect NVX-CoV2373 to offer less protection than if the person sticks with the same vaccine technology for all doses. But it is still unclear if superior efficacy is possible with switching vaccines.

Countries like Germany, Israel, the UK, and the US are deep into planning or executing booster deployment, despite the World Health Organization (WHO) calling for a delay due to worldwide vaccine shortages. Novavax, which has a $17.16bn market cap, did not respond to a comment request.

Vaccine and adjuvant untested in the real world

Since NVX-CoV2373 is yet to be authorised, unexpected side effects could surface once it is used more widely as a heterologous booster, experts said. In the US and Europe, NVX-CoV2373 would be a heterologous booster to authorised shots like mRNA vaccines by Moderna and Pfizer/BioNTech, or adenovirus-vectored vaccines by AstraZeneca or Johnson & Johnson. There is no authorised protein subunit Covid-19 vaccine in the US and Europe, and NVX-CoV2373 is the frontrunner.

Novavax’s vaccine includes an adjuvant, which may have a different safety profile from other parts of NVX-CoV2373, said Center for Clinical Epidemiology and Population Health director Dr Edward Belongia. NVX-CoV2373 features SARS-CoV-2’s full-length spike protein plus the company’s saponin-based Matrix-M adjuvant. Adjuvants can induce side effects related to reactogenicity, Belongia noted. Hence, lymph node-related side effects and their duration need to be monitored, he added.

While Matrix-M is also in Novavax’s own influenza vaccine Nanoflu, it is yet to be a part of any approved vaccine, Belongia said. Novavax in March 2020 reported favourable safety data from its Phase III Nanoflu trial in adults aged 65 years and over. mRNA and adenovirus-vectored vaccines do not require adjuvants.

Millions needed to reveal potential for rare side effects

Even though NVX-CoV2373’s trials recruited thousands of participants, the rare side effects seen with mRNA and adenovirus-vectored Covid-19 vaccines only surfaced once millions of people were vaccinated, and this could also be the case with NVX-CoV2373, added Midwest Biomedical Research chief scientist Dr Kevin Maki.

NVX-CoV2373’s activity is mainly based on two Phase III trials: a 15,187-participant UK-based trial, and the US and Mexico-based 29,960-volunteer PREVENT-19 trial. Despite attempts at diversity, Covid-19 vaccine trials may still not represent the wider population, added Upstate Medical University Department of Microbiology and Immunology interim chair Dr Stephen Thomas.

Nevertheless, NVX-CoV2373’s existing safety profile is encouraging thus far, noted Dr Daniel Griffin, chief of New York-based ProHealth Healthcare’s Division of Infectious Disease. In the UK-based Phase III trial, NVX-CoV2373 reactogenicity was generally mild or moderate. Injection-site tenderness and pain, fatigue, headache, and muscle pain were the most reported adverse events.

Also, combinations of different Covid-19 vaccine technologies have a favourable safety profile, added Ghent University Faculty of Medicine & Health Science professor emeritus Geert Leroux-Roels. In the Com-COV trial combining AstraZeneca’s Vaxzevria (AZD1222) with Pfizer/BioNTech’s Comirnaty (BNT162b2), no safety concerns were raised.

Vaccine switching can circumvent mRNA issues

In fact, NVX-CoV2373 as a heterologous booster could circumvent rare side effect issues that may arise from sticking with an mRNA vaccine as a third dose, noted Thomas, a Phase III Comirnaty investigator. On 23 July, this news service reported more people may experience Covid-19 mRNA vaccines’ rare heart inflammation side effects if they are deployed as boosters. People who had side effects with either mRNA or adenovirus-vectored vaccines, even if short term, may be open to switching technologies if available, Thomas said.

Currently, people are encouraged to stick with the same vaccine technology, even if it may mean waiting for several weeks for subsequent doses, said Edward Dougherty, a principal at his eponymous Washington DC-based healthcare consulting firm. In Europe, however, heterologous vaccine approaches are accepted to reduce side effect risk. While there may be little enthusiasm in the US for a heterologous approach, this could change with more data, he noted.

Protein subunit vaccines longer to make

Allowing NVX-CoV2373 to be used as a booster would diversify options and prevent delays in case other vaccines are in short supply. Yet protein subunit vaccines’ production process is slower than that for mRNA vaccines, noted Dr Zoltán Kis research associate at Imperial College London’s Future Vaccine Manufacturing Hub.

To manufacture protein subunit vaccines, insect cells are grown in large volumes over several weeks, and then infected with baculoviruses that contain the genetic code for the spike protein, Kis explained. Then the spike protein is extracted once it is produced in the cells. Adjuvants are manufactured separately. In comparison, mRNA vaccine manufacturing is speedier and doesn’t require such cells, since they are synthetically processed.

However, protein subunit vaccines use a more conventional technology than mRNA vaccines, so more technicians are familiar with this approach, Kis said. The challenge with mRNA vaccine manufacturing is the necessary upskilling of existing technicians, who are in worldwide shortage, as well as mRNA vaccine manufacturing infrastructure, he added. News reports show Novavax’s delayed progress in securing authorisation is due to the limited resources available to make NVX-CoV2373.

Switching to Novavax as booster unlikely to impact efficacy

NVX-CoV2373 is in several trials investigating it as the second dose of a different vaccine technology (heterologous combination), as well as the third dose in people who have previously received an authorised vaccine (heterologous booster). Using NVX-CoV2373 as a heterologous booster is unlikely to reduce efficacy compared with sticking to the same vaccine technology, experts agreed. Preliminary Phase II data showed that a single booster of NVX-CoV2373 given six months after an initial two-dose regimen of the same vaccine led to a 4.6-fold increase in antibody titers. Additionally, the vaccine was effective against the Delta variant of concern, Novavax noted in early August.

Belongia pointed to the Com-COV trial data showing SARS-CoV-2 antispike IgG concentrations of heterologous vaccines being higher than homologous schedules. More data is needed regarding NVX-CoV2373’s potential to induce immunological memory to further its argument as the ideal booster, added Alabama Vaccine Research Clinic director Dr Paul Goepfert.

Variant-specific vaccine a better sell as booster

Additional doses of the same adenovirus-vectored vaccine may not be as effective due to anti-vector response caused by the initial vaccine schedule, this news service reported 12 February. Experts said NVX-CoV2373 as a heterologous booster can alleviate this issue. That said, it is still unclear if using a different vaccine technology as a booster would improve efficacy as there is little data supporting that, noted Goepfert, a Phase III single-dose JNJ-78436735 investigator.

Novavax’s vaccine as a heterologous booster would be more appealing for policy makers if it were a tweaked version against more pressing variants of concern, added Leroux-Roels, who is an investigator in J&J’s two-dose Covid-19 vaccine trial. Novavax has a version of its vaccine specific for the Beta variant of concern in preclinical investigations. This news service reported 3 May that using a tweaked Covid-19 vaccine would allow for broader immunogenicity profile in the vaccine receiver.