Next Generation Covid Vaccines Update (No 9): Major New Hat in the Ring Plus Important Results

This update is packed with news, with 3 developments standing out in particular. The first is the “major hat” in this post’s title. It’s a new consortium of major scientific groups, along with a major global pharmaceutical company, spanning bases in Israel, the US, and Europe. That’s everything that’s needed for the very heavy – and expensive – lift of running late-stage clinical trials, large-scale manufacturing, and working with regulators that’s needed to get a vaccine on the market. They don’t have a vaccine yet, but the goal is one that can protect not just against Covid-19 and its next variants, but other coronaviruses as well.

Another of the trio of developments is related to pancoronavirus vaccine. An American group that’s been working on this since 2021 have reported preclinical results of a “cocktail” approach that resulted in hamsters being protected against not just recent Omicron strains, but 2 bat coronaviruses as well. They sound optimistic about being able to use this approach to develop a broadly protective next-generation vaccine.

The third is further along. It’s an intranasal booster vaccine, that’s showing signs of providing mucosal immunity in a phase 1 trial – and the university has formed a company to help develop it.

Those highlights and more below, broken down into 3 categories of next-generation Covid vaccines (definitions below).

• Mucosal vaccine news
• Covid-19 “variant-proof” vaccine news
• Pancoronavirus vaccine news
• Addendum 1: Table of mucosal vaccines in clinical trials
• Addendum 2: Table of pancoronavirus vaccines with results
• Addendum 3: Definitions of vaccine types

Mucosal vaccine news

We’ll start with one of the big bits of news I mentioned in the introduction. It’s about the NDV-HXP-S vaccine, developed in the US at Mount Sinai in New York. The vaccine is available for development without royalties in lower income countries, and 4 have developed versions: Brazil, Mexico, Thailand, and Vietnam. Both the original developers, and the team at Avi-Mex in Mexico (where the vaccine is called Patria), have been testing intranasal versions.

This vaccine is a viral vector vaccine, using the Newcastle Disease Virus (either live or inactivated). It couples the ability for old school manufacture – in eggs, like flu vaccine – with Hexapro, a major advance in the way the Covid protein is modified, hoping to be more potent than first-generation vaccines. (Carl Zimmer wrote a great article about this in 2021.)

There are 3 bits of news on this vaccine:

• Mount Sinai have formed a company, called CastleVax, to raise funds and develop the vaccine further;
• A report of preclinical results for the intranasal vaccine in mice was released; and
• In a press release, Mount Sinai said that preliminary analysis of a phase 1 trial in the US showed particularly positive results for the intranasal version.

There’s no data provided on those clinical trial results. According to the registered report for this trial, it’s a small trial (35 participants). The press release says that an intranasal booster resulted in saliva levels showing signs of mucosal immunity, as well as systemic immunity. Better mucosal immunity could help reduce infection and transmission of Covid-19. (Results from a phase 1 trial in Mexico that included intranasal boosting have been published.)

A couple of reports of preclinical results stood out in the last month, too. The first is a report for a vaccine against both Covid and Influenza A from the University of Manitoba. The developers tested their viral vector vaccine in oral and intranasal forms, and concluded results were somewhat similar. (There were only challenge studies for influenza, not Covid.)

Finally, there were preclinical results comparing an intranasal vaccine with Moderna Covid vaccine. The intranasal vaccine (VLP-RBD-BECC) was developed by West Virginia University (USA), and the results were previously available in a preprint. Both protected mice from challenge with the Delta variant, however the developers found less lung inflammation early on for those administered the intranasal vaccine.

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Covid-19 “variant-proof” vaccine news

This category is complicated, because it’s hard to define it properly. There were clinical trial results this month for a vaccine that I think fits at least roughly into the category of trying to provide broad SARS-CoV-2 protection. It’s a tetravalent version of Sinocelltech’s protein subunit vaccine (China).

This report includes preliminary safety and immunogenicity results for a subset of 449 men (and 1 woman) from a small ongoing phase 3 trial. (There is also a 10,000-participant phase trial underway in China for this tetravalent vaccine.)

The tetravalent vaccine, SCTV01E, targets Alpha, Beta, Delta and Omicron BA.1 variants (in a ratio of 1:1:1:3). It was tested as a booster in people who have either had Covid or been vaccinated, and it’s compared to the original version of the BNT/Pfizer vaccine (not a recent one adapted for variants), and SCTV01C – a bivalent version of Sinocelltech’s vaccine (targeting Alpha and Beta), and in a lower dose than the SCTV01E.

The rate of adverse effects for the tetravalent vaccine were lower than for the BNT/Pfizer vaccine, and signs of immune response were stronger, including for BA.5, an Omicron variant that emerged after this vaccine was developed. It’s too soon to know if this equates to better protection, and how that might compare with other Omicron-adapted vaccines.

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Pancoronavirus vaccine news

I mentioned a pair of big developments in this category in the introduction – a new collaboration, and some particularly noteworthy preclinical results from another group.

The new collaboration is between the Sheba Pandemic Research Institute (SPRI) in Israel – itself a new collaboration between Sheba Medical Center in Israel and the NIH’s Vaccine Research Center in the US – and the US Walter Reed Army Institute of Research (WRAIR), as well as Sanofi (a global pharmaceutical manufacturer, based in Europe).

WRAIR has been working on a pancoronavirus vaccine since quite early in the pandemic, and has had one in phase 1 trial. (You can catch up with the research on their 2 vaccines in the table below.) Sheba Medical Center will be contributing their massive database to the effort. They’ve been drawing and cataloging regular blood samples for their over 10,000 staff since before the arrival of SARS-CoV-2 in Israel. So it’s a massive trove of data across waves of variants that the group can analyze, looking for common features.

A spokesperson for the collaboration talked about the possibility of having a vaccine in mid-2024. That’s ambitious. That said, having a major pharmaceutical company interested in the potential vaccine makes that imaginable if it all goes very well.

The other big news in this category comes from the University of Wisconsin-Madison, with a team that’s been getting several considerable NIH grants for this work since 2021. A third report of preclinical results was released from this group, still in non-primates, and this one is worth digging into in some detail.

This group, including people from Georgia Tech, is working on protein subunit vaccines. The developers have moved onto testing vaccines made using “cocktails” of proteins. After testing immune responses in hamsters to vaccines based on single proteins from a wide variety of coronaviruses, they chose those that stimulated the greatest immune responses to a variety of coronaviruses, as well as providing protection in challenge tests. They created a pair of cocktails – a bivalent one, and a trivalent one that had better results.

For the trivalent vaccine, when hamsters were infected with coronaviruses – 2 recent Omicron variants, and 2 bat coronaviruses – they didn’t get sick, and there was no detectable virus in their lungs. They also tested some hamsters vaccinated with a bivalent BNT/Pfizer vaccine, although it was only a single low dose: Those hamsters didn’t generate signs of immune response to the coronaviruses they tested, and they didn’t have enough protection in the challenge tests.

These results convinced the developers that the “cocktail” approach is worth pursuing. They wrote, “this study is a valuable step towards designing a pan-sarbecovirus vaccine.” (Sarbecovirus is the group of coronaviruses that caused both the original SARS and Covid-19.)

I’ve also added a pair of new vaccines to the table of pancoronavirus vaccine efforts with results, one each from France and USA:

• A protein subunit vaccine from Osivax in France, with results in non-primates; and
• Another protein subunit vaccine, from Stanford University. That group has now released results in primates as well as non-primates.

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Addendum 1: 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.

Vaccine, type, manufacturer	Mucosal version(s)	Phase 1 to 2 clinical trials	Phase 3+ trial(s)	Phase 3+ efficacy or immunogenicity results
ACM-001 Protein subunit ACM Biolabs (Singapore/Switzerland) (All records)	Intranasal.	Phase 1.
Ad5-nCoV (Convidecia Air) Viral vector (adenovirus) CanSino (China) (All records)	Inhaled through the mouth using a nebulizer.	Phase 1. Results. Phase 1/2. Results (plus second later preprint). Phase 2 (aged 6-17 years).	10,420 people in China (Phase 3). Results. 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 1. Results – 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).
Avacc 10 Protein subunit Intravacc (Netherlands) (All records)	Intranasal.	Phase 1.
bacTRL-Spike-1 Live attenuated Symvivo (Canada) (All records)	Oral.	Phase 1.
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. Phase 2.	In India, 2-dose course of BBV154 vs 2-dose course of injected Covaxin inactivated vaccine (Phase 3 – and here). Results. See also the drug product information. 875 people in India, booster trial (Phase 3).	2,998 previously unvaxed people were assigned for the intranasal iNCOVACC, 162 for injected Covaxin. This trial did not aim to assess disease outcomes. It took place during the first Omicron wave. Signs of immune response were higher for iNCOVACC than Covaxin. Adverse events rate very low (5% local and 3% systemic) – lower than for comparison group.
BV-AdCoV-1 Viral vector (adenovirus) Wuhan BravoVax (China) (All records)	Inhaled through the mouth using a nebulizer.	Phase 1.
ChAdOx1 Viral vector (adenovirus) Oxford University (UK) (This is the AstraZeneca vax) (All records)	Intranasal.	Phase 1. Phase 1. Results.
CoV2-OGEN1 Protein subunit US Specialty Formulations/VaxForm (USA) (All records)	Oral.	Phase 1. (Fully recruited, final dose in November 2022.)
COVI-VAC Live attenuated Codagenix (USA, with the Serum Institute of India) (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).	Phase 2/3, as part of the WHO Solidarity Trial for Vaccines in Mali. (Protocol.)
CVXGA1-001 Viral vector (parainfluenza) CyanVac/Blue Lake Tech (USA) (All records)	Intranasal.	Phase 1. Phase 2.
DNS1-RBD (Pneucolin) Viral vector (influenza) Beijing Wantai BioPharm (China) (All records)	Intranasal.	Phase 1. Phase 2. Joint results.	30,990 participants in Colombia, Philippines, South Africa, Vietnam. Results. 5,400 participants in Ghana (Phase 3).	Comparison of 2 doses of intranasal vaccine 14 days apart, with placebo control, during circulation of Omicron. Included >13,000 previously unvaccinated people. Efficacy shown 90 days after 2nd dose. There was some decline at 180 days. 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) Adverse events were very low – similar to placebo. Less than 8% of people had a runny and/or blocked nose or sore throat.
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 (report of a conference presentation). 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.
*NDV-HXP-S Viral vector (Newcastle Disease Virus) Castlevax/Icahn Mt Sinai (All records)	Intranasal.	Phase 1. Results (press release).
Patria (NDV-HXP-S/AVX-COVID-12-HEXAPRO) Viral vector (Newcastle Disease Virus) Laboratorio Avi-Mex (Mexico) (All records on Patria, see NDV-HXP-S above for early development.)	Intranasal.	Phase 1. Results. Phase 2. Results (press release).
PRAK-03202 Protein subunit Oravax (USA) [Oravax was established by OraMed (Israel) to develop this vaccine, using Premas Biotech’s PRAK-03202 and their oral vaccine technology] (All records on oral PRAK-03202, and on intramuscular version)	Oral.	Phase 1 (in South Africa). Results (press release only).
Razi Cov Pars Protein subunit Razi Vaccine & Serum Research Institute (Iran) (All records)	Intranasal (third dose after 2 injections).	Phase 1. Results. 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) Moat Bio/Tetherex (USA) (All records)	Intranasal and inhaled.	Phase 1. Trial expanded to add an inhaled version (from 130 to 190 people). Results so far briefly mentioned in press release.
(Unnamed) Inactivated bacteria DreamTec (Hong Kong) (All records)	Oral.	Phase 1. Phase 1. Phase 1. Note: An article of preclinical results has been retracted over lack of ethics committee approval.
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 was developed for an Omicron challenge trial, originally planned for second half of 2023. This vax is now on hold, as Vaxart is trying to develop an oral pan-betacoronavirus vaccine.

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Addendum 2: Pancoronavirus vaccines with preclinical results

* Indicates new entry since previous update post.

Developer Country Vaccine name	Type of: Vaccine Coronavirus	Preclinical results	Clinical trial status
California Institute of Technology (Caltech) USA Mosaic-8b	Protein subunit Beta	Non-primate Non-primate Non-primate Primate, non-primate
Codiak USA exoVACC Pan Beta Coronavirus	Protein subunit Beta	Article on development Non-primate (conference slides) Non-primate (conference slides)	(This company began proceedings in bankruptcy court. See news.)
DIOSynvax UK DIOS-CoVax/ pEVAC-PS	mRNA Sarbeco	Non-primate	Phase 1 trial (incl. protocol) (Up to 36 participants) Began December 2021. Fully recruited. Expanded to another city – no trial register entry found.
Duke University USA RBD–scNP	Protein subunit Beta	Primate Primate, non-primate Non-primate
Francis Crick Institute UK (Unnamed)	Protein subunit with DNA boost All	Non-primate
Fudan University China CF501	Protein subunit Sarbeco	Primate, non-primate Primate Primate
Inserm Vaccine Research Institute France CD40.CoV2	Protein subunit Sarbeco	Non-primate Primate, non-primate Primate Non-primate (conference poster)
Oragenics/Inspirevax/ National Research Council of Canada USA, Canada NT-CoV2-1	Protein subunit (Intranasal) All	Non-primate (original vax) Non-primate (original vax)
* Osivax France OVX033	Protein subunit Sarbeco	Non-primate
Pennsylvania State University USA (Unnamed)	Protein subunit All	Non-primate
Scripps Research Institute USA (Unnamed)	Protein subunit Beta	Non-primate
SK Bioscience/ Uni of Washington/Uni of North Carolina at Chapel Hill South Korea, USA GBP511	Protein subunit Sarbeco	Primate, non-primate (testing Covid vaccine GBP510 against other sarbecoviruses)	(More on plans for adapting this vaccine – GBP510 authorized as SKYCovione.)
* Stanford University USA DCFHP-alum	Protein subunit Sarbeco	Primate Non-primate
University of California Irvine USA (Unnamed)	Viral vector Beta	Non-primate Non-primate (mucosal) (There was also a paper about this vaccine’s development in 2021.)
University of North Carolina at Chapel Hill USA (Unnamed)	Viral vector Sarbeco	Non-primate
University of Toronto Canada (Unnamed)	Protein subunit Sarbeco	Non-primate
University of Wisconsin-Madison (PanCorVac) USA (Unnamed)	Protein subunit All	Non-primate Non-primate * Non-primate
VBI Vaccines Canada VBI-2901	eVLP All	Non-primate Non-primate (Press release)	Phase 1 trial (103 participants) Began October 2022. Fully recruited. (Further background info.)
Walter Reed Army Institute of Research (WRAIR) USA SpFN 1B-06-PL	Protein subunit Beta	Non-primate Non-primate Non-primate (incl RFN) Non-primate Primate Primate Primate (with J&J vax)	Phase 1 trial (29 participants) Began April 2021. Results described as “positive” – no data reported yet. Additional detail on phase 1 trial.
Walter Reed Army Institute of Research (WRAIR) USA RFN	Protein subunit Beta	Non-primate (incl SpFN) Primate
Yale University USA (Unnamed)	mRNA All	Non-primate Non-primate
Yale University/Xanadu Bio USA (Unnamed)	Protein subunit, intranasal booster Sarbeco	Non-primate

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Addendum 3: 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.
• 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: @hildabast@mastodon.online 

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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:

1. Mucosal vaccines (March 2022)
2. Pan-SARS-Cov-2 and pancoronavirus (July 2022)
3. Mucosal vaccines (July 2022)
4. Mucosal vaccines (September 2022)
5. Mucosal vaccines (April 2023)
6. Pancoronavirus vaccines (April 2023)

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.)