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A Huge Boost for Mucosal Covid Vax Development (Next Generation Update 15) [1]
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Date: 2024-03-29
Mucosal vaccines go directly into the mucosal tissue where infection begins – for example, intranasally or via tablets. If they could induce strong enough mucosal immunity, such vaccines could reduce the risk of infection and transmission. That’s often called “sterilizing” immunity.
Development of these vaccines has just received a massive boost. A global consortium is being funded to develop and then run human challenge trials of intranasal or inhaled vaccines in a program called MusiCC. A human challenge trial – where participants are quarantined and deliberately infected in that controlled environment – could find out quickly and definitively establish whether or not particular vaccines can prevent infection and transmission. If very effective vaccines are tested in this program, it would vault them rapidly through development stages that could otherwise take years.
As well, the US Government’s Project NextGen is calling for interest in developing and/or supporting oral Covid vaccines. This pair of new initiatives kick off this month’s update.
There is also some news from clinical trials for 2 intranasal vaccines, as well as development news on 2 vaccines in the “variant-proof” category, and several preclinical studies. Following the news about mucosal vaccine development funding, I have these results broken down into 3 categories of next-generation Covid vaccines (definitions below).
New development initiatives for mucosal vaccines
Mucosal vaccine development news
Durable or “variant-proof” vaccine news
Pancoronavirus vaccine news
Addendum 1: List of authorized vaccines (with countries)
Addendum 2: Table of mucosal vaccines in clinical trials
Addendum 3: Table of pancoronavirus vaccines with results
Addendum 4: Definitions of vaccine types
New development initiatives for mucosal vaccines
In the last few weeks, 2 initiatives aiming to boost the development of mucosal vaccines have been announced – a global human challenge trial program to be led by Imperial College London for inhaled and intranasal vaccines, and a request from US Project NextGen for parties interested in developing or supporting oral Covid vaccines.
Human challenge program: Mucosal Immunity in human Coronavirus Challenge (MusiCC)
This is a new 5-year program led by Imperial College London to speed development and access to mucosal coronavirus vaccines by running placebo-controlled human challenge trials. That involves trying to infect volunteers under controlled conditions, which means trials that can establish whether infection is blocked can be completed quickly, with fewer volunteers than a standard trial.
MusiCC is supported with $57 million from the European Union and CEPI (Coalition for Epidemic Preparedness Innovations). A global consortium of more than a dozen teams and organizations specializing in human challenge studies will be involved. They are interested in inhaled and intranasal vaccines that could block transmission of betacoronaviruses (the virus group including Covid and MERS). The program “includes a commitment that any vaccines developed are made available first and at an affordable price to the most vulnerable populations.”
From the announcement: “Using harmonised standard operating procedures, the trials will take place across several sites in the UK, Europe, the United States and Singapore and will each involve a small group of young, healthy volunteers. In the challenge trial, volunteers will first receive either a dose of an investigational vaccine designed to provide mucosal coronavirus immunity or placebo before being intentionally exposed to a calibrated dose of SARS-CoV-2. A model using a seasonal coronavirus called OC43 is also being developed for similar use.”
The first step is deciding on which variant of SARS-CoV-2 will be used, and then developing a version that can be used in the trials. Imperial College London has done this before. Their team published the results of a Covid human challenge trial with 36 people to test the process. They were able to infect just over half the participants with a version of the original virus (wild type).
The UK government provided funding for that original program, which was announced in October 2020. The trial got the regulatory green light to start in February 2021, and the first participants had left quarantine by March. The government funding for the whole program of which that trial was part, was £33.6 million – in pounds sterling for comparison, this new program is £44 million.
We don’t know yet which vaccines might be involved. Other than Imperial College London, the only other organization named in CEPI’s announcement is University of Antwerp’s Vaccinopolis. A statement from Imperial College London mentions a London hub for trials, and studying the biology of respiratory infection with the National Centre for Infectious Diseases (NCID) in Singapore.
US Project NextGen:
The US Government Project NextGen is seeking parties interested in developing, or supporting, oral Covid vaccines. Their request suggests that oral formulation “could improve vaccine’s efficacy, uptake, compliance, and accessibility.” This funding program aims to address challenges with manufacturing oral vaccines, including “maintaining antigen stability, navigating the gastrointestinal environment, and achieving scalable and cost-effective manufacturing processes.”
Trial funding overview: The original plan for Project NextGen was to fund phase 1 and 2 trials in up to 10 vaccines. I haven’t tried to keep track of how much funding has already been earmarked, so I don’t know how many more awards are possible. They have announced funding for 5 trials so far: phase 1 for TNX-1800 from Tonix (aiming for lifelong immunity); and phase 2 trials for Castlevax (intranasal), Codagenix (intranasal), Gritstone Bio (“variant-proof” self-amplifying mRNA), and Vaxart (oral).
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Mucosal vaccine news
There were 2 sets of clinical trial results for this update. The first was a phase 3 trial of a course of a vaccine with 2 injections plus an intranasal dose, that can’t show whether there was an advantage from dose 3 being intranasal. The second is for a phase 1 trial, but it’s only a press release. Finally, there are 3 preclinical study reports.
Phase 3 clinical trial results: Razi-Cov Pars (Iran)
Razi-Cov Pars (RCP) was the first mucosal Covid vaccine rolled out. It’s a 3-dose protein subunit vaccine, with 2 injections followed by an intranasal dose. The first publication of phase 3 results was released this month. It’s a confusing report of a complex trial, and you need to dig into the supplementary information to see data on the intranasal third dose. It was designed as a non-inferiority trial – aiming to test whether RCP was at least as good as the Sinopharm vaccine, rather than directly estimating efficacy. The trial was stopped early, which further complicates the picture.
As it proved too difficult to recruit enough people to the randomized trial, there was a smaller randomized trial, and a non-randomized trial in which participants could choose which of the 2 vaccines in the trial they received.
There were 7,224 participants in the randomized trial, receiving 2 injections of either RCP or Sinopharm’s inactivated Covid vaccine, followed by an intranasal dose of either RCP or adjuvant only. There were 15,886 participants in the non-randomized trial – in this group, people getting the Sinopharm vaccine got no third dose.
In the randomized trial, 2 weeks after the second injection, 133 had confirmed Covid in the Sinopharm group versus 121 in the RCP group, a hazard ratio of 0.91 (97.5% CI 0.71-1.16). It wasn’t clear how long the follow-up for the third dose was. In that time, the number of participants with confirmed Covid was 123 in the Sinopharm group versus 112 in the RCP group.
The authors reported that they had tried to test for signs of mucosal immune response with a saliva test, but the method was unsatisfactory. The authors concluded that RCP was non-inferior to Sinopharm, with similar very low rates of adverse events.
Phase 1 clinical trial results: Avacc (Netherlands)
This is an intranasal protein subunit vaccine, based on outer membrane vesicles (OMV). The trial was run in Australia, with 36 participants receiving 2 intranasal doses 3 weeks apart, in either low or high dose. It’s reported in a press release only, without data. The release states that there were signs of mucosal immune response in the participants on the high dose.
New preclinical results:
I’ve added 3 preclinical reports on results for mucosal vaccines to my collection since the last update:
Vaxart (USA): This is a viral vector vaccine, and a tablet form is one of the vaccines with Project NextGen funding for a phase 2 trial. The latest study tested 3 versions of the vaccine intranasally in primates, and included a group that received an injection and an intranasal dose. (Records in my collection for this vax here.)
Chengdu Kanghua Biological Products (China): This is also a viral vector vaccine. A study tested an intranasal version in mice, as standalone vaccine or booster.
Osaka University (Japan): This live attenuated virus vaccine was tested in intranasally in hamsters.
Mucosal Covid vaccine overview (no change this month):
Mucosal vaccines are currently authorized for use in 6 countries. However, none have been authorized by a drug regulatory agency designated stringent, or listed, by WHO.
27 have reached clinical trial, although at least one of those has been discontinued. These are tracked in a table below.
6 mucosal vaccines have reached phase 3 trials, including the 5 authorized vaccines, and one from the US.
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Durable or “variant-proof” vaccine news
This month, there was some news on 2 vaccines that have gone head-to-head with the BNT/Pfizer vaccine, and ones I think are worth keeping a close eye on: LUNAR-COV19 from Arcturus, and the GeoVax vaccine, developed by the City of Hope cancer center and the NIH’s National Cancer Institute (NCI).
Note: This is a rather vague category, including vaccines that aim to be more durable. I don’t include a table for tracking these vaccines. That’s because while I’m quite confident I’ve tagged all the vaccines in my collection that fall into the other 2 categories of next generation vaccines, I’m not sure how many can be classified as aiming to be “variant-proof”.
LUNAR-COV19 from Arcturus (USA)
LUNAR-COV19 is a self-amplifying mRNA vaccine, with factories being built by CSL Seqirus in Australia and the US to manufacture it. A phase 3 clinical trial has been registered for a version of this vaccine (ARCT-2303) adapted to the Omicron variant, XBB.1.5, in combination with flu vaccine. It was planned to start in March. It doesn’t say where, but a contract research organization from Melbourne (Australia) is listed.
Rollout of the original version of this vaccine is planned in Japan this year, with the trade name Kostaive. Though the developers reported they had lodged an application with the European Medicines Agency, the Agency hasn’t reported that evaluation has begun. I included an overview of the trials for this vaccine in a previous update. (Records in my collection for this vaccine here.)
GEO-CM04S1 from GeoVax (USA)
This is a viral vector vaccine, based on modified Ankara virus (MVA). It was developed at the City of Hope with the National Cancer Institute, to better serve immunocompromised people on cancer treatment, and the results released so far have been encouraging.
This vaccine is being developed with Geovax. Up to now, the vaccine used in trials has been produced by City of Hope. This month, Geovax reported that their commercial manufacturing system has now produced a batch of this vaccine. No word yet, though, on when this vaccine might head into phase 3. (Records in my collection for this vaccine here.)
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Pancoronavirus vaccine news
Pancoronavirus vaccines aim to provide protection not only from variants of the SARS virus that causes Covid, but also against the next new coronavirus to spread among humans. There were no new studies or results in this category.
However, there was a relevant new preclinical study report. It was from the University of Washington (US) developers of the protein subunit Covid vaccine marketed by SK Bioscience with the trade name SKYCovione. They used the same platform to develop and test a MERS vaccine in mice, and concluded that being able to adapt the vaccine to a second coronavirus suggests it could be adapted to further coronaviruses.
Pancoronavirus vaccine overview:
A table below this post keeps track of vaccines I’ve added to this category so far that have publicly available preclinical results.
There are 5 of these vaccines in phase 1 clinical trials:
DIOSynVax (Cambridge University spin-off, UK) – mRNA.
INSERM/LinkInVax (France) – protein subunit.
Osivax (France) – protein subunit.
VBI Vaccines (Canada) – eVLP.
Walter Reed Army Institute of Research (WRAIR, USA) – protein subunit.
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Addendum 1: List of authorized next generation Covid vaccines (with countries)
There are now 7 next-generation Covid vaccines authorized in 7 countries. Only one has been authorized by a drug regulatory agency designated stringent, or listed, by WHO – it’s in bold. I’ve listed the vaccines in 2 categories, in order of date of first authorization.
Mucosal:
Razi-Cov Pars (Iran), intranasal protein subunit vaccine: Iran (October 2021).
Sputnik (Russia), intranasal viral vector vaccine: Russia (April 2022).
Convidecia (China), inhaled viral vector vaccine: China (September 2022), Morocco (November 2022), Indonesia (March 2023).
iNCOVACC (USA/India), intranasal viral vector vaccine: India (September 2022).
Pneucolin (China), intranasal viral vector vaccine: China (December 2022).
Self-amplifying mRNA:
Gemcovac (India): India (June 2022).
LUNAR-COV19 (USA): Japan (November 2023).
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Addendum 2: Table of mucosal vaccines in clinical trials
* Indicates new entry since my previous update post.
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.
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Addendum 3: Pancoronavirus vaccines with preclinical results
* Indicates new entry since previous update post.
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Addendum 4: Definitions of vaccine types
Mucosal vaccines: These enter the body the way the virus does – through mucosal tissues. It’s hoped that provides defence against infection. They 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.
Pan-SARS-CoV-2 or “variant-proof” vaccines: These aim to provide protection against any variant of the coronavirus that causes Covid-19 – including future variants. I include vaccines that aim for greater durability in this group.
Pancoronavirus can be targeted to: the “subgroup” the 2 SARS viruses came from (the sarbecovirus subgenus), coronaviruses from the next level up (the genus, betacoronavirus, which includes lethal diseases like MERS, as well as common cold viruses), or the whole coronavirus family – it has 4 genuses, including betacoronavirus and alphacoronavirus (with more common cold viruses).
I classify a vaccine as a pancoronavirus one when the developers are explicitly targeting coronaviruses more broadly than SARS-CoV-2, and have tested for signs of response to non-SARS-CoV-2 coronavirus(es) (or clearly plan to).
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You can keep up with my work at my newsletter, Living With Evidence. And I’m active on Mastodon: @
[email protected]
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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.
Previous update posts on next generation Covid vaccines:
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 cartoon is my own (CC BY-NC-ND license). (More cartoons at Statistically Funny.)
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