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Feature Investigation

Covid-19: Whatever happened to the Novavax vaccine?

BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2965 (Published 08 December 2021) Cite this as: BMJ 2021;375:n2965

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Bureaucracy has created a mess for Novavax volunteers like me

  1. Serena Tinari, freelance journalist,
  2. Catherine Riva, freelance journalist
  1. Bern, Switzerland
  1. serena.tinari{at}re-check.ch

Novavax had a vaccine with big promise. Its more traditional technology and easy storage attracted big global investment but, as year two of the pandemic draws to a close, the company struggles with regulators, disappoints hopeful governments, and lags far behind its competitors. Is there still hope, ask Serena Tinari and Catherine Riva

At the start of the covid-19 pandemic a small US drug company found itself in prime position to develop a vaccine.

Before covid, Maryland based Novavax had worked on vaccines against Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), H1N1 influenza, Zika virus, and Ebola virus. As early as January 2020 the biotech firm’s president of research and development, Gregory M Glenn, told the press that it was already developing a vaccine against SARS-CoV-2.

“This type of activity is in our blood,” he said.1

A few weeks later the company’s stocks soared by more than 20% amid claims that it hoped to start clinical trials by the end of the spring. Investment from global and government bodies followed. The Coalition for Epidemic Preparedness Innovations, a public and private alliance to finance and develop vaccines, has given nearly $400m (£300m; €350m) in funding to date. As a result, Novavax planned to send 1.1 billion doses to Covax, the initiative charged with ensuring equitable access to vaccines around the world. In summer 2020 Novavax was awarded $1.6bn to produce up to 100 million doses by Operation Warp Speed, the US government programme to expedite covid vaccines.

It was an impressive feat for a company that had never brought a product to market and did not own a single manufacturing facility at the time.

But fast forward to today and a series of setbacks has left Novavax lagging far behind its industry rivals Pfizer and Moderna. Its vaccine remains unauthorised by a major regulator, and so it cannot deliver doses to Covax or any other government.

The company’s slow progress in production, in comparison with the leading covid vaccine makers, has created doubts as to its ability to fulfil global vaccine orders. Because most middle and high income countries have already sourced their vaccine supply, has Novavax missed the boat?

Early hopes

The Novavax vaccine candidate, NVX-CoV2373, is based on a technology already used in a few approved products. It contains a protein derived from moth cells, and its Matrix-M1 adjuvant is based on a saponin extracted from the Chilean soapbark tree (Quillaja saponaria). Hamid Merchant, professor of pharmacology at the University of Huddersfield, told The BMJ that a saponin was “the secret ingredient behind the success story of the world’s first malaria vaccine that recently met the WHO efficacy targets.” Crucially, the vaccine offers another option in addition to those based on novel technologies, such as Pfizer and Moderna’s products.

And the early signs were hopeful. So much so that in January 2021 a Reuters investigation showed that Stanley Erck, the company’s chief executive officer, Gregory M Glenn, John Trizzino, its chief commercial officer, and John Herrmann, its chief legal officer, had sold roughly $46m of company stocks. Lucrative liquidations were an “opportunity for its executives to lock in big profits from market optimism,” Reuters wrote.2

Early clinical studies in adults showed the vaccine triggered an immune response to SARS-CoV-2. In February 2021, in a press release with no underlying data and noticeably not in a preprint or peer reviewed publication, Novavax issued interim results of its large UK phase III trial, reporting 95.6% efficacy against the original variant of the virus.3 That same month the European Medicines Agency started a rolling review of the vaccine, and in March 2021 Erck said he expected clearance by the US Food and Drug Administration (FDA) “as early as May.”4 Also in May the company published the interim results of a phase II trial that found the efficacy of the vaccine against the South African variant to be 51%.5

The promised May deadline for FDA approval silently vanished. Instead, the company rekindled enthusiasm in June with a poster of a phase III study in US and Mexico, with an efficacy finding of 90.4%.

In Atlantic magazine the scientist commentator Hilda Bastian wrote, “Among several wonderful options, the more old-school vaccine from Novavax combines ease of manufacture with high efficacy and lower side effects. For the moment, it’s the best covid-19 vaccine we have.”6

More press releases followed: the European Commission signed an agreement for up to 100 million doses, with an option for an additional 100 million; and governments’ orders, applications for approval, and further deals were announced in the Philippines, Indonesia, and Japan.

Asked whether she remains enthusiastic, Bastian told The BMJ that it “still looks like one of the contenders for best covid vaccine,” with the provision that, until there’s a rollout, “we won’t know about potential rare adverse effects and duration of effectiveness.”

Bastian adds that Novavax seems to have drawn several short straws in the vaccine race with Moderna and Pfizer. “The US not allowing export of critical basic materials to India appears to have been a major factor,” she says, and, “The US government used the Defense Production Act to solve some of Pfizer’s supply problems.” The underlying issue “may well be rich countries deciding to prioritise their own needs, not global vaccine supply,” Bastian says. “Covax was relying heavily on Novavax, but the countries that could have made sure Novavax got over the line were not.”

As the world opened up, with lockdowns lifting and some travel resuming, Novavax trial participants began to wonder when authorisation would happen, only to be told it would be “soon.”7 Many covid passports, which in some countries are needed to access public events, require evidence of an authorised or approved vaccine, leaving Novavax trial participants essentially grounded. Questions about continued delays began to filter out beyond the business press to the general news media as trial volunteers started to speak out.

Manufacturing issues

How does Novavax explain the delay? Glenn told The BMJ that the company lacked the production expertise of larger corporations: “If I can be a little bit defensive, about two years ago we were a very small company, we didn’t have manufacturing.” Of the production he says, “It’s also somewhat artsy, it takes people with a lot of skills. You can’t just get people off the streets to do it.” Glenn told of struggles with several contractors, some of which worked on clinical trial batches but, for one reason or another, couldn’t keep delivering.

And with each switch of manufacturing facilities came more delay. Merchant told The BMJ that bringing in new manufacturing contractors is considered by regulators to be a “critical change.” He says, “It requires additional studies demonstrating consistency in manufacturing and quality operations and assessment of related risks in efficacy and safety.”

In October a Politico report quoted anonymous sources who had “direct knowledge of the matter” suggesting that Novavax had problems with purity levels.8 Whereas the FDA requests that each batch reach at least 90% purity, manufacturing was showing levels around 70%, one of the sources said. Sources were not confident that Novavax had the resources “to reproduce a high-quality vaccine on a consistent basis” but speculated that it could fix issues and reach licensure by the end of 2022. The company responded with a press release, reaffirming “confidence in our ability to deliver our high-quality vaccine.” After Politico’s article Novavax shares plummeted, which prompted various law firms to launch investigations on behalf of shareholders.

If manufacturing issues and timelines, along with hurdles in the way of getting necessary data to regulators, are a key explanation for the recurring setbacks, how did rival Moderna manage the jump to mass production? Like Novavax, Moderna has been around for about 30 years and, before the pandemic, had no experience of bringing a vaccine to market.

Moderna’s collaboration with the US National Institutes of Health (NIH) might have helped the biotech company get clinical trials on the way quickly. (Moderna and the NIH are, however, currently entrenched in a patent controversy.) Also, Moderna cut multiple deals with the Swiss company Lonza, which owns relatively large manufacturing facilities.

In contrast, Novavax is building a network of manufacturing facilities from scratch. Several plants are listed in the company’s “investor deck” of May 2021.9 In Europe, Novavax has two facilities, one in the Czech Republic and the other in Sweden. This spring the Swedish site, Novavax AB, announced that it had doubled its workforce to 140, with plans to hire more staff. “Our plan is to have a capacity of two billion doses per year . . . The idea is to do all this in one year,” said its chief executive, Magnus Sävenhed.10

Novavax in the meantime announced big production deals, such as a $372m agreement with Polish biotech Mabion. And it initiated one with the Serum Institute of India, although as recently as September 2021 sources told the Indian media that delays were probable. Will all this be sufficient to have NVX-CoV2373 distributed worldwide any time soon?

Has Novavax missed the boat?

Huddersfield University’s Merchant suggests there is no longer a desperate need for an additional vaccine candidate “and hence the emergency use authorisation from the FDA may not be available any more.” Novavax might have missed the boat of the biggest business, as most of the middle to high income countries have already sourced their vaccine quantities. Another example is the withdrawal of an mRNA vaccine candidate by CureVac AG, dropped despite being under EMA’s review.

Cody Meissner, professor of paediatrics at the Tufts University School of Medicine, Boston, Massachusetts, and a member of the FDA’s external advisory committee for vaccines, emphasises the importance of keeping a global perspective in the Novavax saga. If in rich countries supply is now exceeding demand, a very different picture can be seen in other countries, thus “we need all possible vaccines and platforms.” As to whether Novavax might ever be granted FDA authorisation, Meissner pointed to the agency’s recent emergency use authorisation of the Pfizer-BioNTech covid vaccine for 5 to 11 year olds, “and certainly there wasn’t an emergency there.” Meissner added, “Each of the vaccines now available in the UK, EU, and US is associated with side effects. They are very rare, but they do occur. I’m thinking about myocarditis, and vaccine induced thrombosis and thrombocytopenia. Because it is certainly true that no vaccine will be 100% safe, there will always be a risk of reactions, even with the safest vaccine.” And there, the relatively traditional technology used by Novavax may bring advantages, if its jab shows features similar to other protein based biologicals.

Is the finish line finally in sight?

Although social media and investors’ forums share hopeful messages on progress, the delays to the Novavax vaccine have disappointed governments and global organisations. Covax, which had a target of delivering two billion vaccine doses by the end of 2021, had relied heavily on Novavax. The company promised to begin delivering 350 million doses in the third quarter of 2021, subject to regulatory approval. But authorisation by the World Health Organization is still pending, and by September Covax was forced to revise down its supply forecast. By mid-November less than 4.7% of people in low income countries had received one dose, whereas in high income countries the proportion was 73%.

Reports of new delays also keep surfacing. In Australia 51 million doses of the vaccine slated to arrive this year are now not expected until 2022. The Guardian reported that, after initially touting Novavax as a key vaccine, the Australian federal government had since “quietly edged away from the commitment as it focuses instead on securing more Pfizer vaccines.”11 In October Novavax published a preprint with the results of a US and Mexico phase III study reporting 90% efficacy against laboratory confirmed covid-19, “with most cases due to variant strains.”12 The company says the study has been submitted to the New England Journal of Medicine.

The company maintained in its interview with The BMJ that everything was going to be fine, that the vaccine’s discovery was “fantastic,” and that the product was “very robust.” Regulatory agencies contacted by The BMJ were not able to share any specific information on the application status. However, on 27 October Novavax announced that it had finally submitted all missing data to the Medicines and Healthcare Products Regulatory Agency. The UK meanwhile has moved on. As many as 19 000 Novavax UK trial participants are being offered a double dose of an mRNA vaccine, “to ensure they can travel abroad to countries which currently only accept vaccination records with approved vaccinations.”13

As recently as November 2021 Novavax investors’ hopes were revived once again after NVX-CoV2373 received emergency use authorisation in Indonesia and the Philippines, and regulatory submissions were completed in Australia, Canada, New Zealand, the EU, and India and with WHO. In a press release the company said it expects to submit its full regulatory package to the FDA “by the end of the year.” Novavax emphasised to The BMJ that by the end of 2021 it will be able to manufacture 150 million doses a month.

However, time will tell what place Novavax’s product will take in the covid vaccine race. Meissner expects that in the coming times more interest will be on more traditional vaccine platforms, and on adjuvants—like Novavax’s product. He says, “I personally want to see as many platforms tried, and we’ll see which one is going to be the best. The mRNA products hit the finishing line first, but it doesn’t mean it will necessarily be the same in the long run.”

Footnotes

  • Competing interests: We have read and understood the BMJ policy on declaration of interests and declare that we are the cofounders and co-chairs of Re-Check, Investigating and Mapping Health Affairs.

  • Provenance and peer review: Commissioned; externally peer reviewed.

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