Oral Covid vaccine: can Vaxart overcome clinical trial obstacles?
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Vaxart oral Covid-19 vaccine: could trial execution obstacles delay market entry?

By Reynald Castaneda 24 Nov 2021 (Last Updated November 24th, 2021 17:27)

Vaxart’s vaccine could sidestep antivector response concerns and has potential to prevent transmission.

Vaxart oral Covid-19 vaccine: could trial execution obstacles delay market entry?
Vaxart’s Covid-19 vaccine tablet has a coating that allows it to withstand the low pH in the stomach. Credit: Vaxart

Vaxart is aiming to be a vital player in boosting vaccination rates with its oral Covid-19 vaccine. There is still unmet need, with only 53% of the world’s population receiving at least one dose of a Covid-19 vaccine.

The California-based company’s Covid-19 vaccine tablet (VXA-CoV2-1.1-S) has the obvious convenience advantage of not needing a cold chain protocol, as well as doing away with needles, syringes and vials. Also, as Vaxart chief scientific officer Sean Tucker points out, the vaccine has the additional potential benefit of sidestepping unwanted antivector responses as expected with other adenovirus-vectored vaccines. Vaxart uses the adenovirus type 5 (Ad5) as its vector. In addition, there is preclinical data showing its oral vaccine could also prevent SARS-CoV-2 transmission to unvaccinated individuals.

Vaxart chief scientific officer Sean Tucker

But how feasible is it for Vaxart to speed through the development race as seen with already authorised vaccines? Needle-free vaccines are “fanciful”, according to Vaxine chairman and vaccine developer Nikolai Petrovsky. Vaxine recently reported interim Phase III data of its protein subunit vaccine SpikoGen.

At this point of the pandemic, it will be “incredibly difficult” for companies with unvalidated Covid-19 vaccine mechanisms that are still in early-phase clinical trials to gain regulatory support, Petrovsky says. Vaxart is amidst a Phase II trial (NCT05067933) with interim data expected 1Q22. With untested technologies, regulatory authorities will still likely insist on large-scale, Phase III trials, as was done with first-generation vaccines, and these trial designs are getting increasingly harder to run, he adds. This is particularly true in countries that have infrastructure to stage these trials, where a significant chunk of the willing population are already vaccinated, he explains.

With untested technologies, regulatory authorities will still likely insist on large-scale, Phase III trials.

But there is still a need for boosters, Vaxart’s Tucker notes. The company’s Phase II trial is investigating its vaccine as a booster dose in people who have previously received an mRNA vaccine in their primary series. Also, while there are regulatory agencies that are more conservative and would demand such large-scale registrational trials, there may be others who would be open to efficacy endpoints that demonstrate competitive rates of neutralising antibody titers versus an approved vaccine, or even a challenge trial design, he adds.

French company Valneva is one of the first developers to stage a Phase III trial that is not placebo-controlled, or with an endpoint investigating infection rates. Instead, its Phase III test (NCT04864561) had AstraZeneca’s Vaxzevria (AZD1222) as an active comparator, with a primary endpoint comparing both vaccine’s geometric mean titres and seroconversion rates. That said, Valneva’s vaccine is considered a more traditional vaccine technology, with VLA2001 being an inactivated SARS-CoV-2 vaccine.

Potential for a decentralised approach?

Vaxart’s ongoing Phase II is designed to initially recruit 96 subjects from four sites in the US. ClinicalTrials.gov shows the study ultimately aims to recruit 896 participants, with Tucker noting the trial would expand to other countries.

The first 96 participants are divided into two groups: people in the first group have previously received an mRNA vaccine, while the second group includes vaccine-naïve volunteers.

Both groups receive two doses of the oral vaccine administered 29 days apart. While it is possible that participants who have been vaccinated before may only need one booster dose, the two-dose approach will nonetheless investigate the value of a potential fourth vaccine dose, Tucker says.

One of the challenges facing Vaxart is finding unexposed participants.

One of the challenges facing Vaxart is finding unexposed participants, with many people already having received the primary schedule or having been infected previously, Tucker says. Blood tests are done to exclude potential participants who have been infected before but were asymptomatic, he adds.

But overall, Vaxart’s oral vaccine is much more straightforward to investigate in a clinical trial than ones that require a needle and syringe. At one point, it was even considered that the company would fully embrace a decentralised trial design. The vaccine would be delivered via mail and subjects observed during a telemedicine session. Any blood samples would be collected via a finger prick test. But eventually, the company decided it would still be key to have onsite visits to understand the mucosal performance of the vaccine.

Surviving stomach acids is key

Vaxart’s Covid-19 vaccine tablet has a coating that allows it to survive the low pH in the stomach. Once it reaches the lower small intestine, its adenovirus vectors are released to infect epithelial cells. Once the genetic code is delivered, the host cell manufactures the SARS-CoV-2 spike antigen, as well as a double-stranded hairpin turn adjuvant. Vaxart’s vaccine draws a stronger response in the lower small intestine potentially due to specific immune system cells in this region, as well as local digestive enzymes assisting with the response, Tucker explains.

Vaxart’s Covid-19 vaccine tablet features Ad5 that infect epithelial cells in the lower small intestine. Credit: Vaxart

Vaxart uses the Ad5 vector. CanSino Biologics’ single-dose Covid-19 vaccine Convidecia also uses an Ad5 vector, as well as the second dose in the two-dose vaccine Sputnik V. The Russia-developed vaccine’s first dose features an Ad26 vector, which is also used in Johnson & Johnson’s vaccine. AstraZeneca’s vaccine uses a simian adenovirus vector. Apart from Vaxart, all these vaccines are administered via injection.

According to Vaxart’s Phase I data, its vaccine induces mucosal immunity, which includes the nose. Data shows it also has potential in causing broad cross-coronavirus activity. Nevertheless, data revealed there was room to improve on the vaccine’s potential to induce serum antibodies, Tucker notes. The tablet in the Phase II trial has been tweaked to have a more balanced mucosal and serum antibody effect, he adds.

Another observation from the Phase I was that the vaccine has a potent T cell response. But the tablet formulation in the Phase II was also tweaked to ensure that it would have a stronger focus at inducing an antibody response, Tucker says. Both antibody and T cell responses are key in potentially having longer-term protection, he explains.

Several theoretical advantages

One of the main advantages of Vaxart’s Covid-19 vaccine is that it could sidestep unwanted antivector responses, Tucker says. On 12 February, this news service reported that adenovirus-vectored Covid-19 vaccines may face efficacy issues if they are used again as boosters because the immune system would be able to recognise and debilitate the vector.

The immune system is only switched on once the antigen and adjuvant have already been generated.

In Vaxart’s case, with the vector released in the intestine, the immune system is only switched on once the antigen and adjuvant have already been generated, Tucker says. “The vector is not recognised as a foreign protein in the intestine,” he notes, adding this shouldn’t be surprising because the immune system does not mount a defence against food. However, the vaccine is yet to be explored in detail in patients with irritable bowel syndrome or Crohn’s disease.

Another potential advantage of Vaxart’s tablet vaccine is it could prevent transmission. In a preclinical test, the vaccine decreased aerosol transmission from vaccinated to unvaccinated hamsters. It’s been very challenging to develop a nasally administered vaccine, potentially due to the nose’s proximity to the brain, Tucker says.