U.S-based Novavax (Nasdaq: NVAX) reports today that its COVID-19 vaccine candidate called NVX-CoV2373 or “Coronavax” demonstrated 100% protection against moderate and severe disease and 90.4% overall efficacy, keeping this investigational product competitive with both mRNA-based vaccine products under emergency use authorization (EUA) as well as superior to the Johnson and Johnson Adenovirus-based vaccine, which is also authorized for deployment in the USA on an emergency basis. NVX-CoV2373 is a recombinant nanoparticle protein-based experimental vaccine, and could become the first vaccine available in the USA that does not use a gene therapy-based vaccination method. Meeting its clinical trial endpoints during the PREVENT-19 pivotal Phase 3 clinical trial, this study included 29,260 participants across 119 trial site organizations in both America and Mexico. The PREVENT-19 study evaluated the efficacy, safety, and immunogenicity of the Novavax candidate, and focused on the recruitment of study participants who are epidemiologically more likely to be impacted by the disease (e.g. the elderly, minorities, those with co-morbidities). But facing what is considered intense competition in what is increasingly in the USA a COVID-19 vaccine surplus-based market, the company (which is heavily funded by the American government) is today guided by such sages as the New York Times’ Carl Zimmer to seek alternative options other than the standard emergency use authorization (EUA) direct to market pathway here domestically. Assuming the consuming American public will seek the more novel gene-based vaccination products, Zimmer hints at options such as the full registration, which would delay the product’s market entry by many months while also considering export deals such as supplying vaccine product to low-to middle-income countries (LMICs). But TrialSite puts forth a different point of view: that the American public will greatly benefit from this vaccine product brought this far thanks to the funding of CEPI, the Bill and Melinda Gates Foundation, and the U.S. government. With what would be considered a more traditional vaccine potentially ready for the market, a true comparison of COVID-19 vaccine safety signals comparing the more traditional Novavax protein/adjuvant vaccine to the mRNA and recombinant adenovirus technology-based vaccines would be possible by the end of 2021. TrialSite analysis suggests that there is a substantial market for a more traditional vaccine, which may be accepted by US citizens hesitant to accept the mRNA and recombinant adenovirus-based genetic vaccine products, which express SARS-CoV-2 spike protein in the cells and tissues of vaccine recipients.
Today’s Novavax press release is big news, made possible thanks to a confluence of factors and forces, from the development of the underlying science to savvy biotech executive presence to rich funding sources. Novavax shared that the company plans on filing for regulatory authorization by Quarter 3, 2021 (July 1-Sept 30), assuming completion of the final phases of the process qualification and assay validation necessary to meet chemistry, manufacturing, and controls (CMC) requirements.
As mentioned above, the New York Times introduced positioning that perhaps due to market forces the vaccine could be more useful offshore outside of the US; TrialSite begs to differ.
What is NVX-CoV2373?
Also referred to by the tradename “Coronavax”, this prefusion protein vaccine candidate is based on the company’s proprietary nanoparticle technology known as Matrix-M, an adjuvant that boosts immune response, thus triggering greater amounts of SARS-CoV-2 neutralizing antibodies. The candidate product is based on an engineered baculovirus (an insect virus that does not infect animals) which includes a modified SARS-CoV-2 spike protein gene. This recombinant insect virus then infects and introduces Sf9 moth cells, which then causes the spike protein to be produced by these cells and display the protein on their cell membranes (see the Precision Vaccinations report: here). The production process then involves the harvesting and assembly of these cell membranes displaying the spike protein “onto a synthetic lipid nanoparticle about 50 nanometers across each displaying up to 14 spike proteins”, again, as summarized in the Precision Vaccinations report. Using proprietary formulation methods, Novavax then combines this vaccine candidate with their patented saponin-based Matrix-M adjuvant which stimulates the migration and activation of antigen-presenting cells at the injection site, while boosting antigen presentation via local lymph nodes which all works to augment immune response, thus aiding the immunized person to produce sufficient antibodies against SARS-Cov-2.
What about Production Capacity?
According to the company’s position via its press release, the Novavax manufacturing prowess is considerable. Declaring that 100 million doses can be produced per month already by the end of Q3 of this year, they assert that this capacity could rise to 150 million doses per month by the end of Q4 2021.
The PREVENT-19 Study
Called the PREVENT-19 study (NCT04611802), the effort was the result of a collaboration between Novavax and the U.S. Department of Health and Human Services (HHS). The study evaluated the effectiveness, immune response, and safety of the Novavax vaccine product known as NVX-CoV2373. Initially signing up 149 trial site locations, the sponsor ended up working with 119 volunteer-producing trial sites.
Initiated in December 2020, the study was slated for completion in June 2023, but the overall study data will now be available for full analysis. The study protocol targeted 33,000 participants, and the trial ended up thus far enrolling 29,260.
In the placebo-controlled, observer-blinded study randomized 2:1, NVX-CoV2373 demonstrated overall efficacy of 90.4% (95% CI: 82.9, 94.6), achieving its primary endpoint. Seventy-seven cases were observed: 63 in the placebo group and 14 in the vaccine group. All cases observed in the vaccine group were mild as defined by the trial protocol. Ten moderate cases and four severe cases were observed, all in the placebo group, yielding a vaccine efficacy of 100% (95% CI: 87.0, 100) against moderate or severe disease.
Efficacy endpoints were accrued from January 25 through April 30, 2021 — a time when the Alpha (B.1.1.7) variant, first identified in the U.K., became the predominant strain in the U.S. Other strains, including Variants of Interest (VoI) and Variants of Concern (VoC), were also on the rise during the PREVENT-19 endpoint accrual window. Click here for CDC definitions of variants.
Sequence data are available for 54 of the 77 cases. PREVENT-19 met its key secondary endpoint, demonstrating 100% efficacy (95% CI: 80.8, 100) against variants not considered VoC/VoI. Of the sequenced cases, 35 (65%) were VoC, 9 (17%) were VoI, and 10 (19%) were other variants. Against VoC/VoI, which represented 82% of the cases, vaccine efficacy was 93.2% (95% CI: 83.9, 97.1), achieving a key exploratory endpoint of the study. Thirty-eight of the VoC/VoI cases were in the placebo group and 6 were in the vaccine group.
NVX-CoV2373 also showed success among “high-risk” populations (defined as over age 65, under age 65 with certain comorbidities or having life circumstances with frequent COVID-19 exposure): vaccine efficacy was 91.0% (95% CI: 83.6, 95.0), with 62 COVID-19 cases in the placebo group and 13 COVID-19 cases in the vaccine group reported the company in its press release.
Study Endpoints
The primary endpoint for PREVENT-19 was the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) COVID-19 with onset at least 7 days after the second dose in serologically negative (to SARS-CoV-2) adult participants at baseline. The statistical success criterion included a lower bound of 95% CI >30%.
Novavax expects to share further details of the PREVENT-19 trial results as additional data become available. Further analyses of the trial are ongoing and will be shared via preprint servers as well as submitted to peer-review journals for publication.
The placebo-controlled portion of PREVENT-19 continues in adolescents from 12 to less than 18 years of age, which recently completed enrollment with 2,248 participants.
How well does the experimental vaccine work against variants?
According to Yale Medicine, thus far the candidate demonstrates 86.3% efficacy in the UK, which is one location of the circulating B.1.1.7 variant. Yale reported that the experimental vaccine has been 55.4% efficacious thus far in a Phase 2b trial targeting the B.1.351 variant among the HIV-negative study volunteers according to a Novavax press release.
Safety Signals
TrialSite’s been at the forefront of tracking what appears to be safety signals associated with what can be classified as the genetic vaccines covering all thee currently authorized vaccines in the United States. The two mRNA-based vaccines (Moderna and Pfizer-BioNTech) and the adenovirus-based Johnson and Johnson experimental product all are available under the FDA’s emergency use authorization (EUA).
As TrialSite shared recently, there’s growing concern with the mRNA-based vaccines, classified as genetic in nature, that there’s a syndrome of disease symptoms which appear to be related to the spike protein that’s produced by patient’s cells that have either been transfected with vaccine mRNA or transduced by the recombinant adenoviral vaccine. While the spike protein is supposed to remain anchored in the arm, it’s actually freely circulating in at least a subset of vaccinated individuals, and this appears to lead to safety problems from cardiovascular and immune responses and perhaps even death. While none of the deaths are officially connected to the experimental vaccine products, some scientists have started to question such a swift and declarative stance.
In response to what some researchers are calling “Post COVID Gene-based Vaccination Syndromes”, the introduction of a more traditional vaccine such as Coronavax could offer both safety data for meaningful comparison between these genetic-based vaccine products and the more traditional Novavax product, and could also provide an alternative to US citizens who are reluctant to accept vaccines based on these gene-based vaccine technologies.
Kudos to the Collaborative Forces
TrialSite spoke with Dr. Robert Malone, a contributor to the media platform and a highly experienced vaccine and gene therapy expert that has worked as a biochemist, pathologist, molecular virologist and medical doctor for four decades. Malone’s involvement with genetic vaccines for example goes back to the very early days at the Salk Institute where he is widely known to be among the father of the mRNA-based movement.
Dr. Malone told TrialSite that “If the Emergency Use Authorization is granted for the Novavax vaccine, then we will have a unique opportunity to compare the adverse events and safety signals associated with the genetic vaccines (J&J, Moderna and Pfizer) and a more traditional vaccine such as the one developed by Novavax. Thus this affords the CDC and FDA the opportunity to track real world data to determine which aspects of what I call ‘Post COVID Gene-based Vaccination Syndromes” are attributable to transgene-expressed spike protein versus what are attributable to spike protein antigens (such as are present in the Novavax product) in general.”
Malone praised the coming together of scientists, funders, and executives to make this milestone possible, declaring, “I congratulate Stan Erck and Greg Glenn and the Novavax team along with CEPI, the Bill and Melinda Gates Foundation and the U.S. government contributors for making this innovative new vaccine available both domestically and to the world via the COVAX initiative.”
Marketplace and Freedom to Choose
While the domestic US press is talking about the fact that the American COVID-19 vaccine market is overly saturated while other regions and LMICs need vaccines now, another challenging reality has been the slow uptake of vaccination across America caused by what’s known as “vaccine hesitancy.” According to Our World Data, U.S. vaccination rates have crawled to a near standstill and are now stuck at approximately 43.8% of the domestic population willing to accept vaccination. President Joe Biden established the target of at least 70% of Americans with one jab by the 4th of July. While that target may or may not get hit, the challenge is that two doses are necessary for the appropriate efficacy.
The slowdown in part is caused by safety concerns mentioned earlier. Across families and social networks, there are stories of post-COVID vaccination health issues and this contributes to vaccine hesitancy, as does the government’s obfuscation of challenges and issues. That type of behavior serves to reduce trust, as opposed to boosting trust levels and improving faith in the vaccine enterprise.
America needs another product on its market that is a non-genetic-based vaccine for COVID-19. While the Novavax “Coronavax” vaccine may trigger its own set of safety signals, those should and will be compared to the Post COVID Gene-based Vaccination Syndrome signals for a more clear and comprehensive understanding of both how these vaccines work and of potential mechanisms of reactogenicity and adverse events.
Conflict of Interest Challenges?
TrialSite suggests also that the government’s research arm, namely the National Institutes of Health (NIH), maintains a close relationship with the mRNA-based vaccines. Stories are circulating of Dr. Anthony Fauci lobbying Nancy Pelosi for funding of mRNA-based products with promises of safety.
Moreover, as NIH/NIAID participated in the Moderna vaccine’s development and hence claims some ownership, both political, capital, and financial ties exist between the nation’s research arm under Fauci and the mRNA-based vaccine maker Moderna as explained in a number of sources.
Francis Collins, NIH’s director, did share during an Economic Club interview in May that “We do have some particular stake in the intellectual property” behind the Moderna mRNA-based vaccine.
Research & Development Executive Lead
Gregory M. Glenn, MD, serves as Novavax’ President of Research and Development and shared on the record for the company’s press release “PREVENT-19 confirms that NVX-CoV2373 offers a reassuring tolerability and safety profile”. “These data show consistent, high levels of efficacy and reaffirm the ability of the vaccine to prevent COVID-19 amid ongoing genetic evolution of the virus. Our vaccine will be a critical part of the solution to COVID-19 and we are grateful to the study participants and trial staff who made this study possible, as well as our supporters, including the U.S. Government.”
While CEO and President Stanley C. Erck shared, “Today, Novavax is one step closer to addressing the critical and persistent global public health need for additional COVID-19 vaccines. These clinical results reinforce that NVX-CoV2373 is extremely effective and offers complete protection against both moderate and severe COVID-19 infection.” Erck continued, “Novavax continues to work with a sense of urgency to complete our regulatory submissions and deliver this vaccine, built on a well understood and proven platform, to a world that is still in great need of vaccines.”TrialSite completely agrees that the world is still in great need of vaccines designed to prevent COVID-19 disease, to reduce the continued spread of SARS-CoV-2, and eliminate the development and spread of vaccine-resistant viral escape mutants.