A Covid Nasal Vaccine Update

Now 6 Ongoing Clinical Trials in the United States

It’s a huge unmet need to prevent Covid infections and block transmission. A nasal spray vaccine has the best shot of achieving this goal, as we’ve seen in many experimental models of candidate vaccines. I’ve reviewed the topic, rationale, and progress previously at Ground Truths, but it has been awhile and there are some interesting new developments, along with concerns about the jeopardy of these program with the new US administration. While SARS-CoV-2 circulating levels are relatively low at the moment, that is not likely to last as the virus’s evolution marches on.

This week the Ocugen Phase 1 trial of an adenovirus-vector spike protein nasal vaccine was given the go ahead by the FDA. This nasal spray vaccine was already approved in India, with ongoing trials, and actually is a work product of the Washington University lab of Michael Diamond, out-licensed to Bharat Biotech in India. Now a US-based company (Ocugen) has proceeded with an application to get it FDA-approved here. That makes it the 6th Covid nasal vaccine to go into clinical trials in the United States.

Here is a Table that summarizes the 6 different nasal vaccines with ongoing trials in the United States.

Let me review the status of each of these:

1. Castlevax, a spinout/intellectual property from Mt. Sinai, Icahn School of Medicine in New York City, supported by Biomedical Advanced Research and Development Authority (BARDA)/Project Nextgen with $34 million. The viral vector is a live, attenuated Newcastle disease (a para-myxo virus-induced disease in chickens with asymptomatic or only mild, self-limiting impact in humans) expressing a SARS-CoV-2 spike protein stabilized by 6-prolines (rather than 2 in the current mRNA shots) to amp up the immune response. A small Phase 1 trial was completed but not yet published, yet data were available to BARDA. A Phase 2 randomized trial of 10,000 participants, half getting the nasal vaccine and half assigned to a shot, is in progress. A recent publication showed a single nasal vaccine administration completely blocked transmission of multiple variants of SARS-CoV-2 (including recent ones like KP.2) in 2 animal models (hamsters and mice). Interim results of a Phase 3 trial conducted in Mexico with this nasal vaccine showed comparable results as an intramuscular shot, but not published. A 4,000 participant randomized trial is underway in Thailand. Exact status of the US large trial enrollment is unclear other than data provided at clinicaltrials.gov.

2. Codagenix completed a Phase 1 trial of 48 participants with its live, attenuated SARS-CoV-2 virus that indicated it elicited solid immune response. The vaccine has an ongoing large randomized trial supported by the World Health Organization SOLIDARITY clinic trial consortium, and has an ongoing Phase 2B trial in the US. It is supported by BARDA/Project NextGen.

3. Cynavac/Blue Lake, supported by BARDA/Project Nextgen with $40 million recently started a Phase 2B 10,000 participant randomized trial on December 5, 2024. Expected to complete enrollment by June 2026, and final completion in 2027. It is a double-blind, randomized trial comparing this parainfluenza viral vector delivery of the spike protein vs Moderna’s intramuscular shot. The primary endpoint is prevention of Covid infections.

4. National Institute of Allergy and Infectious Diseases (NIAID) has a Phase 1 ongoing trial of a live, attenuated parainfluenza virus with 6P spike protein (6P proline substitution reviewed in prior post) at Johns Hopkins in 2 sequential doses, open label, 27 participants, started enrollment in 2023 and should be complete by now, yet results are unpublished..

5. National Institute of Allergy and Infectious Diseases has a Phase 1 ongoing trial of a murine pneumonia virus vector spike protein (2P) that is supported by BARDA/Project Next Gen after rodent and non-human primate models showed a strong immunogenicity response and lack of safety issue. The trial is enrolling 60 participants, open-label, dose escalation as a booster to shots.

6. Ocugen is bringing back to the US the Bharat Biotech nasal vaccine that was conceived and had preclinical assessment by Washington University, and subsequently tested in clinical trials and made commercially available in India. As mentioned at the top of this post, just this week FDA approved the go ahead with a Phase 1 trial. It will enroll 80 adults testing 2 different doses of the nasal vaccine and an orally inhaled version. In India, a Phase 3 randomized trial in over 3,000 participants was published demonstrating a robust immune response as a booster compared with a shot. The clinical outcomes of that trial have not yet been published.

Other Related Programs

There are many other nasal Covid vaccines that are being assessed in other countries. For example, In JCI Insight, in China, 128 health care workers were given 2 doses of a nasal vaccine spray, one month apart, at the end of 2022, after prior vaccination. The vaccine is an adenovirus vector that is replication-incompetent, directed against the Omicron BA.1 spike. As it turns out, this nasal vaccine induced more than 50-fold increase in spike-specific IgA secretory antibodies, indicative of achieving potent mucosal immunity. This was seen and consistent against 10 different variants of SARSCoV2.

Moat Bio has a Covid nasal vaccine program in Australia; the initial work was done by Mayo Clinic. There are also early clinical trials in Finland (Rokote), the Netherlands (Intravacc), Singapore and Switzerland (ACM), and they are available in Russia, Cuba, and Iran but without published data that I have seen or could find.

On the related topic of achieving mucosal immunity via oral, inhalation Covid vaccines, there is Aerovax, given as an aerosol. It uses a adenovirus vector but instead of only expressing the spike protein S1 subunit, it also expressed the nucleocapsid and RNA polymerase genes. It is proceeding with a Phase 2 trial in 350 participants. It is a Canada-based program led at McMaster University. Many other inhalation Covid vaccine programs are ongoing in China, Israel (Oravax), Australia (Vaxine), Germany, and other countries.

Vaxart recently released its interim results of a Phase 2B randomized, double-blind oral vaccine pill and is moving ahead with a 10,000 participant trial. It isn’t clear how this route-induced mucosal immunity compares with nasal or inhalation strategies.

Meissa, a spinout of Emory University, had very encouraging results in multiple experimental models, including nonhuman primates using a nasally delivered attenuated RSV vector expressing the spike. But the company ran into financial troubles and has not been able to move into clinical trials.

GeoVax is moving forward , supported by BARDA/NextGen, with a vaccine shot (not oral or nasal) specifically to rev up the immune response in immunocompromised individuals

Related Publications or Preprints, Not Covid-Specific

—The challenges of achieving a durable immune response with a nasal vaccine (Figure) were succinctly laid out in this recent Nature Biotech essay.

—Report of an effective nasal vaccine vs flu in experimental models, and another example here.

—A self-amplifying RNA nasal vaccine was highly effective against H5N1 and H7N9 influenza in mice and ferrets, but intramuscular shots were not.

Summing Up

It’s great that there are now 6 different programs with ongoing clinical trials in the United States to move Covid nasal vaccines forward, giving us multiple shots on goal (no pun intended) to have at least one that’s effective and safe. We’re far behind where we should be at this point, 5 years into the Covid era, because mucosal vaccines (nasal or oral) have never been a priority, like shots were with Operation Warp Speed. Specific funding for them was not approved by Congress, and it took the Project NextGen allocation to provide support for the 3 programs that are now furthest along—Castlevax, Cynavac, and Codagenix.

These programs are into large randomized trials, with a goal of enrolling 10,000 participants. It is hard to understand why they are categorized as “Phase 2B” since successful completion of a trial of this size would ordinarily be considered as definitive, Phase 3 evidence of efficacy, assuming the results were positive.

That brings up the first challenge. The levels of circulating SARS-CoV-2 are low now, which will slow enrollment (reduced concern and awareness) and the number of outcomes (prevention of infections, the primary endpoint of the trials). Support for the clinical trial infrastructure is the big expense of the programs (hundreds of millions of dollars kicks in) that will only increase with slower, longer duration of trial execution.

The second challenge is touched on in the Nature Biotech piece above. Even though we’ve seen multiple Covid vaccines protective against infections in animal models of mice, hamsters, and nonhuman primates, proving that in people, with durable protection (such as a vaccine spray every 3 or 4 months), remains to be seen. I am optimistic this goal will be achieved for SARS-CoV-2 from the totality of evidence we have so far, but we’re at least a year away from the read outs from the programs that are the furthest along. The only way this delay could be reduced would be for Bharat Biotech’s trial data of clinical efficacy (not just immune response) to be made available (we still haven’t seen it and, in general, publications of all these programs have been scant or markedly delayed) and used to support Ocugen’s FDA application. However, that is quite unlikely. Note I have only highlighted the 6 programs in the US, since nasal vaccine programs in other countries are unlikely to get authorized here without trials conducted in the US.

Perhaps the most formidable and third challenge is the continued US support for the Covid nasal vaccines. The 3 programs that are in late stage trials are all supported by BARDA/Project NextGen. The two Phase 1 trials at NIH are also government subsidized. With the new administration, and potential disregard for continued waves of Covid in the future, along with a policy that does not support any vaccines, no less reduced NIH support for research, there is serious jeopardy of all of the work toward Covid nasal vaccines. Withdrawing support for these programs would essentially pull the rug out for any hope to have a nasal Covid vaccine in the US over the foreseeable future.

***************************************

Thanks for reading and subscribing to Ground Truths.

If you found this interesting please share it!

That makes the work involved in putting these together especially worthwhile.

All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.