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Intranasal & Co: A Very Big Month for Mucosal Covid Vaccines

Cartoon of squirting vax telling Coronavirus I am no jab

Authorization for another 2 new vaccines, a potentially critical international licensing deal, and a new phase 3 trial: This month saw a burst of major developments in the race for Covid mucosal, or “sterilizing”, immunity. There’s also been some new clinical and preclinical data in the last couple of months, and 3 more vaccines could reach authorization this year. So even though we still don’t have the major clinical efficacy results we need, there’s lots to catch up on!

Mucosal vaccines aren’t injected into the blood: they enter our bodies in the same way as the coronavirus does – through the mucosal tissues. The vaccines can be squirts or drops in the nose, inhaled through the mouth through a nebulizer (similar to an asthma medication), or in tablet, capsule, or sublingual form. The goal is to mount a stronger line of defense against SARS-CoV-2 at the virus’ point of entry and so reduce transmission. The 4 mucosal Covid vaccines now authorized for use, each in a single country, are intranasal or inhaled. We’ll start with those and the new licensing deal for one of them for the US, Europe, and Japan, and then check out 20 mucosal vaccines in clinical trials, and recent results:

Update on authorizations and licensing news

The first mucosal Covid vaccine was authorized in Iran at the end of October 2021. It’s an intranasal protein unit vaccine called Razi Cov Pars, that follows 2 injections of the same vaccine. In April this year, Russia authorized a 2-dose course of Sputnik Nasal, the first viral vector component of Sputnik V. In the first week of September, they were joined by another 2 viral vector vaccines, authorized within a day of each other.

The first of the new pair, CanSino’s inhaled vaccine, was authorized in China. Called Convidecia Air, it’s inhaled through the mouth using a nebulizer, like an asthma medication.

Then India authorized an intranasal version of ChAd-SARS-CoV-2-S manufactured by Bharat Biotech. Called iNCOVACC, it involves several drops of vaccine in each nostril. ChAd-SARS-CoV-2-S is based on chimpanzee adenovirus, and it was developed in the US by Washington University in St Louis, with Precision Virologics and some funding from the NIH’s NIAID. The US developers have published results of their tests in mice, hamsters, and macaques. There’s still no full data report of any of the clinical trials from India, though there’s a little in the drug product information, which I discuss later.

On September 28, the US biotech Ocugen announced that they have an exclusive license to develop, manufacture, and commercialize ChAd-SARS-CoV-2-S intranasal vaccine in the US, Europe, and Japan.

What about WHO authorization and mucosal vaccines? As of the end of September, none appear to be under evaluation there yet. The developers of the Iranian Ravi-Cov-Pars vaccine have requested evaluation. CanSino’s injected version was authorized in May. Sputnik V’s injections remain on hold. Medigen has requested evaluation, presumably of its injected version, with the Australian drug regulator listed as evaluator – the Australian regulator announced it was evaluating the vaccine in November 2021.

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Clinical trial overview and frontrunners

Although my posts usually focus on vaccines with study results available, in this post, I’m focusing on vaccine progress by charting those in clinical trials, whether or not there are any preclinical or clinical results available. I found 20, including a vaccine that was discontinued after phase 1. This table breaks all 20 down by the furthest clinical trial phase they’ve reached. (The details are in this post’s addendum.)

Phase 1Phase 2Phase 3
1136

The 6 vaccines in phase 3 include the 4 that have been authorized, as discussed above. Those 4 authorized vaccines could potentially be joined by another 3 vaccines this year or early next year: they’re the other 2 in phase 3, as well as a vaccine that will apply for authorized based on a phase 2 trial. And a couple of US mucosal vaccines are heading into phase 3 trials, one possibly this year, and the other planning for a human challenge trial next year.

Those 3 possibly reaching authorization in 2022 or early next year are:

  • An intranasal viral vector vaccine from Beijing Wantai BioPharm;
  • Mambisa, an intranasal protein subunit vaccine from Cuba; and
  • Patria, an intranasal viral vector vaccine from Mexico, using a vaccine developed in the US.

The influenza-based vaccine from Wantai BioPharm is the mucosal vaccine in the largest placebo-controlled phase 3 trial, planned for 40,000 participants in Colombia, the Philippines, and South Africa. Their trial registration listed the end of April 2022 as the goal for full recruitment. A news report from Vietnam in April said the company was recruiting there and in Indonesia until the end of the month. Although I couldn’t find any report of how it’s going, it’s possible that it’s fully recruited. There’s also a trial for 5,400 participants registered for Ghana. Given the track record of authorizations for Covid vaccines in China based on early data, that could be on the horizon. (Results for phase 1 and 2 trials for this vaccine have been published.)

The Mambisa vaccine was developed by Cuba’s Center for Genetic Engineering and Biotech (CIGB), who also developed the injected vaccine, Abdala. CIGB is reportedly currently analyzing the data from up to 3,000 tourism and healthcare workers who participated in a phase 2 trial comparing an intranasal Mambisa booster with an Abdala booster for people previously Abdala-vaxed. They plan to apply for authorization based on those results. (There was an earlier press release based on results of a phase 1/2 trial of intranasal spray or drops.)

The new phase 3 trial that started this month is for Mexico’s Patria vaccine, for 3,860 people, with hopes it could be rolled out later this year for use in winter. It’s a version of the non-profit viral vector vaccine (Newcastle Disease-based using Hexapro) developed by the Icahn School of Medicine in New York. In August, Avi-Mex reported that the phase 2 trial had shown that Patria worked as a booster, but data weren’t included in the press release.

Behind those, come another 2 vaccines developed in the US, a live attenuated intranasal vaccine from Codagenix, and a viral vector vaccine (adenovirus-based) in tablet form from Vaxart.

According to the developer, Codagenix, the intranasal vaccine was planned to start dosing in a phase 2/3 trial in the middle of this year in the WHO Solidarity Trial for Vaccines. That is a phase 3 trial, currently underway in Colombia, Mali, and the Philippines, but there’s no more information on whether the intranasal vaccine is already included. A company spokesperson has said its phase 2/3 trial is underway in Africa. There’s been no new data on this vaccine that I can find since a conference presentation for the first phase 1 trial last November. A second phase 1 trial in the UK, using it as a booster, had fully recruited between February and June this year. Codagenix has partnered with the Serum Institute of India.

The other is an oral vaccine by Vaxart. They recently announced some early results for a phase trial, that’s still recruiting in the US (discussed later). Vaxart isn’t going straight into phase 3 trial though. They are developing and testing an Omicron-adapted version, as well as bivalent versions (original plus Omicron-adapted), and they expect to take one of those to phase 3 trial in the second half of 2023. Although that start is around a year off, results should come quickly: it will be an Omicron challenge trial, where participants will be infected with the virus. A company in the UK is currently working on developing the Omicron challenge virus for them. The company says there will also be larger trials in the US and internationally.

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Recent clinical and preclinical results

Very little clinical data has been released other than for the 2 Chinese vaccines, and most of the phase 3 trials are relatively small trials comparing signs of immunity rather than disease outcomes. The trial for the Iranian vaccine was a large one with Covid outcomes, in comparison with BBIBP, Sinopharm’s Beijing vaccine (an inactivated vax), but I could only find press reports on those results.

Evaluating the vaccines in trials of manageable size is complicated, because there isn’t an accepted way to reliably measure mucosal immunity. Some of the studies report measurement of antibodies in saliva, but we don’t know if those levels predict the impact on virus transmission. You can dig into all the clinical trials and whatever results are available in the table for all 20 vaccines in this post’s addendum.

There have been some new reports in the last 2 months:

  • Some clinical reports for Bharat Biotech’s iNCOVACC, Mexico’s Patria, and the US Vaxart, but no full publications or agency evaluations; and
  • Preclinical studies for iNCOVACC and Russia’s Sputnik Nasal, as well as for 4 vaccines new to my collection (from Japan, Singapore, Spain, and Sweden).

There are brief sections on the outcomes of the clinical trials for iNCOVACC in the drug’s product information. That included a small amount of neutralizing antibody data only, presumably levels in the blood – which was the trial’s primary outcome – not saliva, for 3,141 people in the phase 3 trial. This trial only had a very small comparison group. Participants had never been Covid-vaccinated, and got either a 2-dose course of intranasal iNCOVACC or a 2-dose course of injections of Bharat Biotech’s inactivated vaccine, Covaxin.

Levels of neutralizing antibodies were lower than for people in the comparison group on the day of administration, but higher on day 42. The vaccine’s outcome was reportedly satisfactory for Beta, Delta, and Omicron, but no data was provided. The vaccine reportedly prevents infection in upper airways, but no phase 3 data was provided on this either. The rate of adverse events was reportedly very low, as it was lower than for the comparison group, but the data provided wasn’t adequate.

In August, the developers of Mexico’s Patria vaccine, Avi-Mex, issued a press release about the phase 2 trial. They reported that there were no safety concerns, and Patria could induce neutralizing antibodies, but didn’t include any data. According to the trial’s register entry, it was for 158 participants who had previously been Covid-vaxed. They got a booster of intranasal or injected Patria, or intranasal or injected placebo. People in the placebo group later got a booster dose of the AstraZeneca vaccine.

Vaxart recently announced results of the first group in their phase 2 trial (press release only). That trial is still recruiting people in the US, aiming for 896 participants. The results released included 66 people getting 2 tablets – some of them had previously been vaccinated with Moderna or Pfizer vaccine. About half had “at least a 1.5-fold increase in mucosal IgA antibodies” against original SARS-CoV-2, including those who had previously been mRNA-vaxed, with some response to Omicron.

There are also new mucosal vaccine preclinical results since the last post – all the first we’ve seen for those vaccines:

  • From the Statens Serum Institute/Karolinska Institute of Sweden, results for injection followed by intranasal dose of a protein subunit vaccine (HexaPro, and adjuvanted).
  • From EP Mediate in Japan, results for a sublingual (under the tongue) protein subunit vaccine with adjuvant.
  • From Duke-National University of Singapore, results for a protein subunit vaccine with adjuvant.
  • From Spain’s Centro Nacional de Biotecnología (CNB), results for an intranasal viral vector vaccine (MVA-based).
  • Results for Bharat Biotech’s iNCOVACC intranasal vaccine as a booster after Bharat Biotech’s Covaxin inactivated vaccine.
  • Results for Sputnik V, intranasal doses compared to intramuscular doses.

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Addendum: 20 mucosal Covid vaccines in clinical trials

Note: Where there is a link to “All records” for a vaccine, that’s in my public Zotero collection for vaccines with results (or in phase 3 trials even if no earlier results are available). Notes on that collection are here. For details on how I track Covid vaccine progress to maintain that collection, see my background post.

Vaccine, type, manufacturerMucosal version(s)Phase 1 to 2 clinical trialsPhase 3+ trial(s)Phase 3+ efficacy or immunogenicity results
ACM-001
Protein subunit

ACM Biolabs (Singapore)
(All records)
Intranasal.Phase 1.
Ad5-nCoV (Convidecia Air)
Viral vector (adenovirus)

CanSino (China)
(All records)
Inhaled through the mouth using a nebulizer, as a booster.Phase 1. Results.

Phase 1/2. Results (plus second later preprint).

Phase 2 (aged 6-17 years).
10,420 people in China (Phase 3).

1,350 people (Phase 3).

540 people, in Malaysia (Phase 3).

904 people in China (Phase 4).
Results.

360 people (Phase 4).
Comparison after 2-dose course of inactivated vax: Convidecia injection vs inhaled, protein subunit, or CoronaVac booster (Phase 4 results). Both injected & inhaled Convidecia had stronger impact on signs of immunity than the others; response after inhaled version was slower but longer-lasting than injected (which peaked then declined from day 14), better for Omicron though not as good for original virus. No measure of mucosal immunity used.
Ad5-triCoV/Mac & ChAd-triCoV/Mac
Viral vector (adenovirus)

McMaster University/Canadian Institutes of Health Research (Canada)
Aerosol.Phase 1.

AdCOVID
Viral vector (adenovirus)

AltImmune (USA)
(All records)
Intranasal.Phase 1Results – press release only.Discontinued after phase 1.
AdS+N
Viral vector (adenovirus)

ImmunityBio (USA)
(All records)

Intranasal, oral capsule, or sublingual.Phase 1 (oral).

Phase 1 (sublingual).
BBV154 (iNCOVACC)
Viral vector (adenovirus)

Bharat Biotech (India)
(All records)
Intranasal.Phase 1.

Phase 2.

Small amount of data from these trials in the drug product information.

Phase 2/3.
3,160 people in India, 2-dose course of BBV154 vs 2-dose course of injected Covaxin inactivated vaccine (Phase 3 – and here).

875 people in India, booster trial (Phase 3).
Small amount of neutralizing antibody data only, presumably serum (trial primary outcome), for 3,141 people in the drug product information: lower than for Covaxin on day of administration but higher on day 42. Reportedly satisfactory for Beta, Delta, and Omicron, but no data provided. Reportedly prevents infection in upper airways, but no data provided.

Adverse events rate very low – lower than for comparison group (Covaxin inactivated vaccine).
ChAdOx1*
Viral vector (adenovirus)

Oxford University (UK)
(* the AstraZeneca vax)
(All records)
Intranasal.Phase 1.

Phase 1.
CoviLiv
Live attenuated

Codagenix (USA)
(All records)
Intranasal.
Phase 1.
Press release stating successful (without data) and progressing to phase 2/3.
Results (conference abstract) and in press release.

Phase 1 (booster).
Announcement of joining WHO Solidarity Trial – currently Colombia, Mali, Philippines. To be powered for 150 cases of Covid-19. (Protocol.)
CVXGA1-001
Viral vector (parainfluenza)

CyanVac (USA)
(All records)
Intranasal.Phase 1.
DNS1-RBD
Viral vector (influenza)

Beijing Wantai BioPharm (China)
(All records)
Intranasal.Phase 1.
Phase 2.
Joint results.
40,000 participants in Colombia, Philippines, South Africa (Phase 3). Planned to recruit by the end of April 2022 – added Indonesia and Vietnam in April, recruiting to the end of the month.

5,400 participants in Ghana (Phase 3).
GAM-COVID-VAC (rAd26-S – Sputnik Light)
Viral vector (adenovirus)

Gamaleya Research Institute (Russia)
Intranasal.Phase 1/2
7,000 participants in Russia (Phase 3 or phase 2/3 – not clear).
Mambisa
Protein subunit

Centre for Genetic Engineering & Biotechnology (CIGB) (Cuba)
(All records)
Intranasal drops.Phase 1/2.

Phase 1/2.
Results (press release only).

Phase 2.
MV-014-212
Viral vector
(RSV)

Meissa Vaccines (USA)
(All records)
Intranasal drops or spray. Phase 1.
Results (press release).
MVA-SARS-2ST
Viral vector (MVA)

German Centre for Infection Research (DZIF)/IDT Biologika
(All records)
Inhalation.Phase 1.
Patria (NDV-HXP-S/AVX-COVID-12-HEXAPRO)
Viral vector (Newcastle Disease Virus)

Laboratorio Avi-Mex (Mexico)
(All records on Patria, early development of NDV-HXP-S)

Intranasal.Phase 1.
Results.

Phase 2.
Results (press release).
Currently recruiting in Mexico, for up to 3,860 participants (press release).
Razi Cov Pars
Protein subunit

Razi Vaccine & Serum Research Institute (Iran)
(All records)
Intranasal (third dose after 2 injections).Phase 1.

Phase 2.

Phase 1 to 2 (in 12-17 year-olds).
41,128 people in Iran, comparing the 3-dose course to 2-dose inactivated Sinopharm Beijing vax (Phase 3). (Press report of results, in the first 24,000 participants.)There were no hospitalizations for Covid in the Razi Cov Pars group and 5 in the Sinopharm group. The rate of Covid was reportedly more than twice as high in the Sinopharm group.
SC-Ad6-1
Viral vector (adenovirus)

Tetherex (USA)
(All records)
Intranasal.Phase 1.
(Unnamed)
Inactivated bacteria

DreamTec (Hong Kong)
(All records)
Oral.Phase 1.
Phase 1.
Phase 1.
VXA-CoV2-1/VXA-CoV2-1.1-S
Viral vector
(adenovirus)

Vaxart (USA)
(All records)
Tablets.Phase 1.
Results.

Phase 2. (Recruiting: started October 1, 2021.)
Results (press release).
Omicron adaptation being developed, Omicron challenge trial planned for second half of 2023.

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~~~~

For details on how I track Covid vaccine progress, see my background post. Notes on my collection of studies are here. The collection is in a public Zotero library you can dig into here.

Cartoon of facing off coronavirus


All my Absolutely Maybe Covid-19 vaccine posts

All previous Covid-19 posts at Absolutely Maybe

My posts at The Atlanticat WIRED, and debunking posts at my personal website.

Disclosures: My interest in Covid-19 vaccine trials is as a person worried about the virus, as my son is immunocompromised: I have no financial or professional interest in the vaccines. I have worked for an institute of the NIH in the past, but not the one working on vaccines (NIAID). More about me.

The cartoons are my own (CC BY-NC-ND license). (More cartoons at Statistically Funny.)

Discussion
  1. Thanks so much for your posts on this subject! I always follow your blog for keeping myself up to date on vaccine development. I am also immunocompromised, and better vaccines are my hope for a more normal life! So your work is precious!

  2. I don’t know how you pull this off but you are the only source I can find that has comprehensive review of intranasal vaccine development like this. Thank you! I too hope that there will be an intranasal vaccine that stops transmission so things can be better. Would you be updating this on a regular basis going forward?

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