Versatility Key to Rapid COVID-19 Vaccine Development

Less than a month ago, while preparing to write this story, I visited the New York Times website for data on COVID-19 vaccine development. At the time, 98 candidate vaccines were in clinical trials. At any other time describing the coronavirus vaccine market as "saturated" would have been an understatement. It's hard to see how even 10 additional vaccines could be profitable, given the natural course of viral pandemics, much less another 100.

Yet as of this writing, the number of development-stage coronavirus vaccines is 111. Did you know that there even were 111 vaccine companies capable of entering clinical trials just months after a health threat was identified? Given that only four candidates out of 115 have thus far failed in the clinic, we could normally expect to see a very crowded market.

In other words, forget everything you have been told for the past 30 years about drug approvals, established technology and risk mitigation, profitability and market share, manufacturing and packaging capacity, the "dying" blockbuster model, me-too drugs, candidate attrition, timelines, and generally any market study containing the words, "The market for…"

One positive, and something that is not too difficult to understand, is how massive investment can spur innovation. That, perhaps, is the real lesson here. Under different circumstances, perhaps those 111 candidates would be award-winning science projects, or part of a PowerPoint presentation for investors. Our current situation demands they all be taken seriously.

Platform versatility

SARS-CoV-2 has thus far followed a typical evolutionary course for pandemic viruses in that emerging variants are more transmissible, but with mortality rates comparable to that of the original strain. Nevertheless, the suspicion that the virus may not be following this trajectory and may mutate to a more lethal bug with higher mortality, has taken hold among stakeholders and public health officials following a better-safe-than-sorry policy.

Only three options exist for developing vaccines against new strains: starting from scratch; wishing and hoping that existing vaccines provide adequate immunity against the new variants; or turning to platform technologies to come up with a new vaccine in short order.

BioVaxys Technology, which specializes in haptenized protein vaccines, is "assessing steps" it can take to modify BVX-0320, its SARS-CoV-2 vaccine candidate, to address emerging coronavirus strains. Haptens are small-molecule compounds that, when bound to an antigen, induce a robust, protective immune response. Haptenization also allows facile creation of multivalent vaccines that presumably would confer immunity to any number of variants. BioVaxys is investigating how to achieve a vaccine incorporating haptenized spike protein subunits from each clinically significant SARS-CoV-2 variant.

BioVaxys expects that a multivalent vaccine based on haptenized spike proteins from these variants would have the same effectiveness that was previously demonstrated in the company's monovalent BVX-0320 vaccine in a mouse model: a 96.4% spike protein-binding antibody response, activation of CD4+ helper T cells and CD8+ killer T cells, and stimulation of T cells that produce gamma interferon. Helper CD4+ T-cells are memory cells that retain information about the virus, enabling them to respond rapidly after viral exposure. CD8+ T cells have the capacity to kill cells infected by the virus, thereby stopping viral replication in those cells.

According to David Berd, M.D., Chief Medical Officer of BioVaxys, "It is likely that T cells induced by the original viral spike protein would also react with the new variants, even though the antibody response is attenuated.”

BioVaxys is also planning to extend the capabilities of Covid-T™, its low cost, disposable, diagnostic for screening T-cell activation responses to the dominant strain of SARS-CoV-2, to additionally screen for T-cell responses to newly emerging SARS-CoV-2 variants such as the South African and UK strains.

Tests like Covid-T are essential for rapid vaccine development because they provide insight into the longer-lasting non-antibody immune response, which for other viruses has been known to last for decades.

Covid-T differs from serologic antibody assays and PCR amplification of viral DNA in that it focuses not on measuring virus particles or neutralizing antibodies, whose presence may or may not be noteworthy, but on T-cell activation in response to SARS-CoV-2, which is typically indicative of a longer lasting immune response. Most notably, the test can be used to evaluate the effectiveness of any SARS-CoV-2 vaccine candidate in stimulating crucial T-cell immunity. Covid-T thus complements antibody and viral load testing. Current T-cell screens require a blood draw and subsequent sample testing through a clinical laboratory.

Plug and play

The same versatility that allows BioVaxys to extend its vaccine to emerging strains is applicable to pathogens other than coronavirus. Those 111 candidate vaccines will certainly not all reach pharmacy shelves, but their developers are learning a lot about working under desperate time constraints. The fallout from all those programs will not be 80 or 90 new coronavirus vaccines but perhaps a dozen or more vaccines to address other unmet healthcare needs.

Vaxart, for example, claims its VAAST (Vector-Adjuvant-Antigen Standardized Technology) oral delivery platform could find potential uses against a wide range of mucosal pathogens. "VAAST uses a non-replicating Ad5 viral vector, which delivers the vaccine to epithelial cells lining the mucosa of the small bowel," says Sean Tucker, Ph.D., founder and Chief Scientific Officer at Vaxart. "Once the pathogen is identified and its genome sequenced, we could potentially have a vaccine ready within months. It’s as simple as plugging in that information and performing the appropriate preclinical studies to select the ideal clinical candidate."

Oral delivery is much sought-after in medicine but has been limited principally to small-molecule drugs, and then only for molecules meeting certain physicochemical criteria. Oral delivery of biologics has been discussed for decades, but its realization has been elusive, particularly for peptide and protein drugs that break down in the digestive system. A vaccine pill or tablet would eliminate nearly all the logistics and compliance issues related, for example, to mass vaccination campaigns such as the one the world is currently undergoing. Note that oral polio vaccines developed in the 1950s were taken by mouth but they used liquid suspensions of live attenuated or inactivated viruses. The Salk vaccine, for example, still required refrigeration and was not self-administered but delivered by healthcare workers.

"Oral delivery is indeed a new approach to vaccines, and as such significant groundwork must be in place to understand early signs of efficacy, to expedite clinical development," Tucker tells Biocompare. "We’ve started to lay that foundation in our non-COVID clinical trials, which have revealed exciting facets of immune biology."

For example, Tucker found that for typical intramuscular vaccines, the best correlative of protection is levels of IgG serum antibodies. "However, in a flu challenge study, we found that for our vaccine the best correlative of protection was IgA-producing cells in the lungs. These results are not surprising given our vaccine targets mucosal tissues. However, they highlight the importance of establishing a baseline for evaluating future potential vaccines from our platform."

The scientific and production methodologies for achieving this level of understanding are already in place, but challenges exist as well. Manufacturing millions of doses of solid dosage form vaccines requires large-scale lyophilization, for which Vaxart has partnered with Attwill Medical Solutions, a contract manufacturer.

"While many things have changed due to the current pandemic, much work remains to establish the metrics to evaluate our vaccines," Tucker says. "Overall, the pandemic has highlighted the importance of platform technology that can rapidly and repeatably be adapted to develop vaccines capable of combating emerging pathogens to prevent an outbreak from becoming a pandemic. Furthermore, the challenges of mass vaccination campaigns have never been more readily apparent and highlight the potential benefits a room temperature stable tablet vaccine has over traditional injectable vaccines."