(C) PLOS One
This story was originally published by PLOS One and is unaltered.
. . . . . . . . . .
Progress on Intranasal & Oral Covid Vaccines – Plus a US Government Funding Boost [1]
[]
Date: 2023-04-21
The race for a vaccine that might be able to provide at least some “sterilizing” immunity just got a boost in the US: A new $5 billion program from the White House called “Project Next Gen” is partly dedicated to speeding up mucosal vaccines. We don’t know yet, though, which vaccines will get the government’s push. One US company already has a candidate in phase 3 trial, and others could be ready to advance clinical trials. Internationally, a handful of mucosal vaccines are already in use, more than a dozen others are in clinical trials, and results of preclinical studies have been released for well over a hundred more, including several developed with or by the US NIH.
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 administered via different routes – 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. Like injected Covid vaccines, though, there are different types, and their efficacy might vary greatly. The route can affect efficacy, too, and so could the person’s current level of immunity – which previous vaccines they have had, for example.
Once it was clear that the effectiveness of the first generation of vaccines waned over time, and variants challenged them as well, interest in intranasal vaccines grew. Interest was already high for other reasons: Mucosal vaccines might be easier (and thus cheaper) to store and deliver, for example.
In theory, then, mucosal vaccines could make an important difference – but we don’t know for sure if they can deliver on all those hopes. It’s already clear, though, that there’s going to be a wide range of results from vaccine to vaccine, just as there was with injected Covid vaccines.
It’s been over 6 months since my last update on these vaccines, and so there’s a fair bit of news to dig into. The post starts with an overview summarizing progress and the current landscape, with more detail in later sections of this post:
Overview
There has been progress on several fronts in the months since my last post on mucosal vaccines (September 2022):
1 more vaccine has been authorized in China – Pneucolin, a viral vector nasal spray from Beijing Wantai BioPharm. There are now 5 mucosal vaccines in use in 4 countries: China, India, Iran, and Russia.
4 more vaccines have entered clinical trials, bringing the total to 24. They are: an intranasal protein subunit vaccine from Intravacc (Netherlands), an oral live attenuated vaccine from Symvivo (Canada), an oral protein subunit vaccine from USSF/VaxForm (US), and an inhaled viral vector vaccine from Wuhan BravoVax (China).
Most of the vaccines in clinical trials are viral vector vaccines. There have been preclinical studies released at least on most vaccine types, including Moderna’s mRNA vaccine.
1 more vaccine has progressed to phase 2 trial – an intranasal viral vector vaccine from CyanVac (US). It’s the fourth mucosal vaccine at that stage.
An oral vaccine in phase 2 has reportedly been put on hold, as its manufacturer, Vaxart (US), switches to developing an oral pancoronavirus vaccine.
No additional vaccine has advanced into phase 3 trials. There are still 6 that reached that point, 5 of which have been authorized in one country each.
The sixth mucosal vaccine in phase 3 is a live attenuated nasal spray from Codagenix (US), being manufactured by the Serum Institute of India. Codagenix hopes it could roll out next year.
CIGB (Cuba), the manufacturers of Mambisa, an intranasal protein subunit vaccine, have reported to a conference that immune responses have been high in their trial. (They are reportedly going to seek authorization based on phase 2 trial results.)
Publications on mucosal vaccines are growing quickly. There are now more than 150 published reports of preclinical studies of mucosal Covid vaccines.
There have been 2 more reports of phase 1 trial results, bringing the total to 7. They are: For the AstraZeneca viral vector vaccine in intranasal form. Immune response was inadequate, and that vaccine hasn’t progressed to further trials. For Razi Cov Pars, the protein subunit vaccine booster from Iran that was the first mucosal vaccine authorized internationally. The trial determined which of 3 doses would progress.
The first articles with phase 3 trial results have been released for: iNCOVACC, an intranasal viral vector vaccine developed in the US. It is authorized in Bharat Biotech’s version in India. A trial in India assessed immune responses, concluding it was superior to Bharat Biotech’s inactivated vaccine, Covaxin. Pneucolin, a nasal spray of a viral vector vaccine developed by Beijing Wantai BioPharm and now authorized in China: Vaccine efficacy against symptomatic infection in Omicron waves was similar to some injected vaccines – around 55%. Additional vaccine efficacy as a booster was lower, especially for people who were previously mRNA-mvaccinated. Efficacy against severe Covid was substantial, however, and around 100% for hospitalization (though with a lot of uncertainty, as few people were hospitalized). Adverse events were very low, and similar to placebo. Less than 8% had reactions in the nose or throat.
(There’s a discussion of the potential and challenges of developing and testing these in a just-published report of a national US workshop from November.)
Back to contents
Authorized mucosal vaccines
Another mucosal Covid vaccine was authorized in December 2022 – and it’s the one with the largest placebo-controlled phase 3 trial (discussed later). Its trade name is Pneucolin, and it’s an intranasal viral vector vaccine, based on the influenza virus, developed by Beijing Wantai BioPharm. The company reportedly plans to produce 200 million doses in the first 6 months.
Pneucolin was the fifth mucosal Covid vaccine authorized internationally, and the second in China. Here are all 5, in order of authorization:
Razi Cov Pars: intranasal protein unit vaccine, authorized in Iran at the end of October 2021. It follows 2 injections of the same vaccine.
Sputnik Nasal: the first viral vector component of Sputnik V (Gam-Covid-Vac) used intranasally, authorized in Russia in April 2022.
Convidecia Air: CanSino’s viral vector vaccine (Ad5-nCoV), inhaled with a nebulizer, authorized in China in September 2022.
iNCOVACC: intranasal viral vector vaccine (ChAd-SARS-CoV-2-S) by Bharat Biotech authorized in India in September 2022. (This vaccine was developed in the US, and US biotech Ocugen announced in September that they have an exclusive license to develop, manufacture, and commercialize this vaccine in the US, Europe, and Japan.)
Pneucolin: intranasal viral vector vaccine (DNS1-RBD), by Beijing Wantai BioPharm, authorized in China in December 2022.
Back to contents
Clinical trial progress
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, and whether not the vaccine is still being developed. I found 24. This table breaks them all down by the furthest clinical trial phase they have reached at the time of writing, as well as vaccine type. (The details are in this post’s addendum.)
Phase 1 Phase 2 Phase 3 14 4 6 Viral vector (8)
Protein subunit (4)
Live attenuated (1)
Inactivated (1) Viral vector (3)
Protein subunit (1) Viral vector (4)
Protein subunit (1)
Live attenuated (1)
Most of these vaccines are based on viral vectors. (You can read up about vaccine types here.) None are mRNA vaccines. Moderna released results of a preclinical study of an intranasal version of their mRNA vaccine in January, but developing a mucosal vaccine hasn’t been featuring as a priority at their website.
Since my last post, no additional vaccine has advanced to phase 3. However, last time I reported that Codagenix had announced their live attenuated intranasal vaccine had joined the WHO Solidarity Trial for Vaccines (STV) as a phase 2/3 trial, but I couldn’t find confirmation. I found it since then at a website for the trial in Mali. Recruitment began there, apparently in August 2022, apparently for a single dose of the nasal spray. The STV is a phase 3 trial for multiple vaccines, sharing a placebo group. It’s an event-driven trial – the goal isn’t achieving a particular recruitment number, but continuing until enough people have had Covid (the “event”) to give a solid answer to the trial’s questions. Participants are contacted weekly to check up on their Covid status.
The Codagenix vaccine is the one by the US manufacturer that I mentioned earlier. It’s a live attenuated vaccine, using a “disabled” form of the virus, and a company’s spokesperson has said they hope to roll it out next year if all goes well – but without mentioning which country or countries they are aiming for. (The company ran phase 1 trials in the UK.)
The other 5 mucosal vaccines that have reached phase 3 trials are the ones that have also already been authorized. Unless another vaccine leaps ahead, that puts Codagenix next to potentially cross the line – along with Mambisa, the intranasal vaccine from CIGB in Cuba. The manufacturers had said they were going to seek authorization from the Cuban drug regulator based on phase 2 results. They recently presented results at a conference, and reportedly said signs of immune response in the nasal mucosal tissue was high. (It’s not yet been established, though, that this translates to reduced risk of infection.)
Another of the manufacturers with advanced plans was Vaxart, who had planned a human challenge trial for their oral vaccine in 2023. However, they have now reportedly put that vaccine on hold, turning their attention to developing an oral pan-betacoronavirus vaccine instead. (That’s the group of coronaviruses that includes both SARS viruses and MERS – update post on these coming soon.)
Since my last post, a vaccine advanced to phase 2: CyanVac’s intranasal parainfluenza-based viral vector vaccine. CyanVac is a US company, and a trial for 400 people was registered in February – it didn’t appear to be recruiting yet as I was writing.
I’ve added 5 more vaccines in phase 1 clinical trials – one which I had missed in my last post, and 4 that recently moved into clinical trial:
Intravacc’s Avacc 10. This is an intranasal protein subunit vaccine, from a Dutch company. The phase 1 trial is in Australia.
Oravax’s oral vaccine (PRAK-03202) had been in phase 1 for some time – it’s the one I missed previously. Oravax is a US company formed by Oramed (Israel) to develop this Covid vaccine. The phase 1 trial is in South Africa. (Some preliminary results are included in the next section of this post.)
Symvivo’s bacTRL-Spike-1. This is an oral live attenuated vaccine, from a Canadian company. The phase 1 trial is in Australia.
USSF/VaxForm – an oral protein subunit vaccine from the US. The phase 1 trial is in New Zealand.
Wuhan BravoVax’s BV-AdCoV-1. This is an inhaled viral vector vaccine, from a Chinese company. The phase 1 trial is in Singapore.
Back to contents
Recent clinical and preclinical results
Since my last post, reports have been released for 4 clinical trials, each for different vaccines – 2 phase 1 trials, and 2 for phase 3 trials.
Phase 1 results:
ChAdOx1 – the AstraZeneca vaccine (viral vector, UK): Results for 36 people, including some as a booster. The vaccine didn’t stimulate adequate immune responses, so the vaccine did not progress to another trial.
Razi Cov Pars (subunit vaccine, Iran): Results for 153 people in a trial of 2 injections and a third intranasal dose. The study tested 3 dosages: The middle dose was the one selected for further trials. (This became the first mucosal vaccine authorized internationally.)
Phase 3 results were released for 2 intranasal viral vector vaccines (both preprints), both of which were run during Omicron waves:
iNCOVACC (ChAd-SARS-CoV-2-S), manufactured by Bharat Biotech in India. The virus vector is adenovirus.
Pneucolin (DNS1-RBD), manufactured by Beijing Wantai BioPharm in China. The virus vector is influenza.
The goals of the iNCOVACC trial were signs of immune response, not Covid outcomes. Around 3,000 previously unvaccinated people got 2 nasal vaccine doses, and 162 got another Bharat Biotech Covid vaccine for comparison – the inactivated vaccine, Covaxin. Signs of immune response were superior for the nasal vaccine, and adverse events were very low.
The Pneucolin trial reports the first Covid outcomes for a mucosal vaccine so far. Before we get into its results, if you’d like an explainer of the terms I use, including the way the statistics and uncertainty are shown, I have a short explainer here. And for context as we look at results, below are some estimates of the effectiveness of injected vaccines against Omicron – they are broadly similar to the estimates from CDC studies:
Vaccination with mRNA plus boosters was estimated to be around 50% effectiveness against laboratory-confirmed infection after mRNA vaccination plus boosters – a bit higher for Moderna than BNT/Pfizer. Results from a case control study based on record linkage in Spain, with over 3 million matched pairs.
For people without compromised immune systems, mRNA vaccination was under 40% effectiveness against hospitalization for Covid, and around 65% effectiveness with one or two boosters. Effectiveness was a bit higher for people with immunocompromise. Booster effectiveness peaked at 4 weeks (waning from then). Results from a test negative study of 4,760 people admitted to US hospitals with acute respiratory symptoms, so there’s a lot more uncertainty around these estimates than first study.
Back to the Pneucolin trial. It was a placebo-controlled trial with 30,990 participants in Colombia, Philippines, South Africa, and Vietnam, about 13,000 of whom were previously unvaccinated. Running this trial was complicated, and so interpreting it as well.
For example, the countries had different vaccines in their primary vaccination programs, so people in the booster groups were systematically different in more ways than whether they were in the placebo group or not – and there were large inconsistencies in how long it had been since people had been vaccinated. It’s a big trial, but because there was such a variety of previous vaccination statuses, there’s a lot of uncertainty around specific outcomes.
Adverse events were very low in the trial – similar to placebo. Less than 8% of people had a runny and/or blocked nose or sore throat. These are the efficacy rates reported:
Efficacy against symptomatic Covid: No previous vax: 55.2% (CI 13.8 to 76.7) Inactivated: 38.2% (CI -49.2 to 74.4) Viral vector: 39.9% (CI -16.7 to 69.1) mRNA: 10.1% (CI -45.9 to 44.5)
Efficacy against severe Covid: No previous vax: 66.7% (CI 8.3 to 87.9) Inactivated: 54.6% (CI -47.3 to 86.0) Viral vector: 50.0% (CI -6.8 to 76.6) mRNA: 19.5% (CI -39.2 to 53.4)
Efficacy against hospitalization: 100% (CI -9.2 to 100)
Preclinical results for mucosal Covid vaccines are coming in quite large numbers. (You can browse over 150 preclinical results I’ve found for mucosal vaccines here.) Here are new reports of preclinical results for vaccines that are also already in clinical trials:
ACM-001 (ACM Biolabs’ intranasal protein subunit vaccine, Singapore/Switzerland): Results.
BV-AdCoV-1 (Wuhan BravoVax’s orally inhaled viral vector vaccine, China): Results.
COVI-VAC (Codagenix’s intranasal live attenuated vaccine, USA, manufactured by the Serum Institute of India): Pediatric results.
iNCOVACC (Bharat Biotech’s intranasal viral vector vaccine, India – vaccine developed in the US): Results.
Pneucolin (DNS1-RBD) (Beijing Wantai BioPharm’s intranasal viral vector vaccine, China): Results.
Vaxart’s oral viral vector vaccine, USA – now on hold: Results.
Add the Moderna preclinical paper.
Back to contents
Addendum: 24 mucosal Covid vaccines in clinical trials
* Indicates a new vaccine, or a new entry for a previously listed vaccine, since my last update post on mucosal vaccines.
Note: Where there is a link to “All records” for a vaccine, that’s in my public Zotero collection for the vaccine, and it may include non-mucosal studies for that vaccine. Notes on that collection are here. For details on how I track Covid vaccine progress to maintain that collection, see my background post.
Back to contents
You can keep up with my work at my newsletter, Living With Evidence. And I’m active on Mastodon: @
[email protected]
~~~~
Update April 22, 2023: I overlooked Intravacc’s vaccine going into phase 1 in my original post. Many thanks to @
[email protected] for pointing out my oversight.
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.
All my Absolutely Maybe Covid-19 vaccine posts
All previous Covid-19 posts at Absolutely Maybe
My posts at The Atlantic, at 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.)
[END]
---
[1] Url:
https://absolutelymaybe.plos.org/2023/04/21/progress-on-intranasal-oral-covid-vaccines-plus-a-us-government-funding-boost/
Published and (C) by PLOS One
Content appears here under this condition or license: Creative Commons - Attribution BY 4.0.
via Magical.Fish Gopher News Feeds:
gopher://magical.fish/1/feeds/news/plosone/
