More Next Generation Covid Vaccines Are Heading Into Clinical Trials (Update 10)

This month, we got news that another couple of next generation vaccines are heading into human trials, both with national research agency support – an intranasal vaccine from the US, and a pancoronavirus vaccine from France. The US government’s Project NextGen announced that a billion dollars is available to support a network of vaccine trials. And according to a company report, the first public results for a clinical trial of a pancoronavirus vaccine could be around the corner.

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

• Update on US Project NextGen
• 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

Update on US Project NextGen

First, a recap. In May, the US government-funded Project NextGen was announced, with US$5 billion for public partnerships to develop better Covid vaccines and treatments (more on this in my June update). At the end of June, journalists reported that about 70 companies had responded (not only on vaccines). Back then, it was expected that there would be eventually be support for early-to-mid-stage clinical trials of up to 10 vaccines, with shared protocols and systems.

The first funding recipients were announced earlier this week, although we still don’t know which vaccines are likely to get the boost. US$1 billion was awarded to 4 companies that run clinical trials, to be ready to run phase 2b vaccine trials. The aim is to “speed the development of new vaccine candidates, providing a network of at-the-ready trials with the flexibility to pivot to the most promising new vaccines as they mature. The public can expect to see clinical trials for new vaccine candidates targeting longer-lasting protection against future variants as early as this winter under Project NextGen.”

Phase 1 trials are first-in-human trials, testing safety and helping establish dosages. Phase 2 trials are mid-stage – bigger than phase 1, but not as big as a phase 3 trials for establishing efficacy. Phase 2b trials are small efficacy trials, midway between phases 2 and 3. That means Project NextGen isn’t going to get a vaccine all the way through to FDA approval: Manufacturers will need to do that bit of heavy lifting.

What vaccines could be ready for phase 2b in the US by the end of year? There are more than half a dozen mucosal vaccines from US developers that are at least as far along as fully-recruited phase 1 trials in the table below. There’s not enough published data from most of them though, so it’s hard to know which might be going well enough to justify an efficacy trial. Nor do we know which groups want to run their trial with Project NextGen.

One stands out, though – NDV-HXP-S, the vaccine that inspired the cartoon at the head of this post. It’s developed at Mt Sinai in New York, and is available non-profit for development in lower income countries – 4 have used it.

Some background on this vaccine (from a previous post): It couples old school, widely accessible technology – the vaccine can be mass-produced in eggs the way flu vaccines are – with a major advance in the way the virus spike is modified. It’s a viral vector vaccine based on the Newcastle Disease virus (NDV) and the Hexapro spike (HXP-S), which is a modification of the spike protein that could make this vaccine particularly potent. A license from the University of Texas at Austin developers of HXP-S is available to low and middle countries without royalties, and the Mt-Sinai-developed NDV platform is also non-profit. There’s a must-read article on this vaccine by Carl Zimmer in the New York Times.

Last year, Mount Sinai announced the formation of Castlevax to develop this vaccine commercially. Although we’ve only seen press release reports for them, there are phase 1 trial results for an intranasal version in the US, as well as phase 2 trial results for the intranasal version developed in Mexico. It’s not the only possibility, but it’s definitely one to look out for in the news.

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Mucosal vaccine news

One of the vaccines headed into clinical trials is an intranasal vax developed by the US National Institutes of Health (NIH). The development was announced by Dartmouth, who will be working on the vaccine and its trials, and Exothera, a manufacturer from Belgium that has been commissioned to produce enough of the vaccine for the trials. The trials will be phase 1/2, in Africa and the US.

Researchers at the NIH have been involved in the development of several vaccines with published results, but I haven’t been able to pin down for sure which vaccine this is – or if anything has been published about it. The Exothera press release says it’s based on adenovirus 4, but also mentions live, non-replicating virus. I’ll be on the lookout for more details.

Someone on Mastodon, whose post I lost track of (apologies!), alerted me to a media report in the US that developers of the Washington University in St Louis (WUSL) intranasal vaccine expect it to “be ready to be presented to the FDA in the United States by the end of the year.” I’m not sure what that means, but it seems to me it could be early steps in the process, not an application for approval.

This vaccine is an adenoviral vector vaccine, developed in the US under the name ChAd-SARS-CoV-2-S. It was used by Bharat Biotech in India to develop a vaccine called iNCOVACC there – authorized for use there in September 2022 (making it the third mucosal vaccine to be rolled out globally). However, the amount of trial evidence accepted in India isn’t necessarily going to be enough in the US. Bharat Biotech published results of their phase 3 trial this month – in January, those results were released in a preprint, so it’s been included in the last few updates here.

We’re still waiting to hear from the FDA on specific requirements for approving Covid vaccines – the emergency use authorization expires later this year. I had a look at the most recently FDA-approved vaccine for non-pregnant adults: That was approved with a placebo-controlled phase 3 trial with 25,000 participants. The phase 3 trial for iNCOVACC had only around 3,000 people, with fewer than 200 in a control group.

This month, the developers from WUSL released a fourth report of preclinical results. In that study, hamsters vaccinated with ChAd-SARS-CoV-2-S were in contact with both vaccinated and unvaccinated hamsters. The developers concluded that while the intranasal vaccine didn’t completely stop virus transmission, it had the potential to interrupt transmission – the animals that showed signs of the virus didn’t have a high enough viral load to transmit it to others in turn.

(This vaccine is listed in the table below as BBV154 (iNCOVACC).)

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Covid-19 “variant-proof” vaccine news

I didn’t see new developments or results for vaccines in this category. Gritstone Bio reported to investors, however, that they expect to release more results from their phase 1 trials later this year. This is a self-amplifying mRNA vaccine that has 3 phase 1 trials in progress, including with some NIH funding. More on what we know so far in my Update 8.

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Pancoronavirus vaccine news

As far as I know, there are still only 3 vaccines in this category in phase 1 trials: an mRNA vaccine from DIOSynvax (Cambridge University, UK); a virus-like particle vaccine (eVLP) from VBI Vaccines (Canada); and a protein subunit vaccine from the Walter Reed Army Institute of Research (USA). A VBI Vaccines company report said they expect to have interim results of their phase 1 trial by the end of September – if so, that’s the first time we’ll see trial results for a pancoronavirus vaccine.

As mentioned above, a fourth pancoronavirus vaccine is heading into a phase 1 clinical trial, expected to start in early 2024. Developed by France’s INSERM, the national health and medical research institution, it has now been named PanCov. INSERM has partnered with LinKinVax to manufacture the protein subunit vaccine for the trial. The records I have for this vaccine are here – and you can see the slides of a presentation the developers made to the WHO in 2022 here.

This month there were preclinical results for 2 pancoronavirus vaccines, both from China:

• There were results in mice for an intranasal vaccine from Sun Yat-Sen University. It is a mosaic nanoparticle vaccine – a method for carrying fragments from multiple different versions of coronaviruses. This one includes RBD fragments of 6 SARS-CoV-2 variants – the original, Delta, and 4 Omicron variants. Mice developed signs of immune response to more than 6 Covid variants, as well as original SARS.
• Results in mice for a protein subunit vaccine with an adjuvant, from Fudan University. The mice developed signs of immune response to SARS-CoV-2 variants, original SARS, and other coronaviruses, including MERS. This was the fourth set of results in my database from this group.

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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) * This vaccine is ChAd-SARS-CoV-2-S Washington University in St Louis (USA) (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 (previously a preprint). See also the drug product information. 875 people in India, booster trial (Phase 3).	2,971 previously unvaxed people were assigned for the intranasal iNCOVACC, 161 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 HR1LS	Protein subunit Sarbeco	Primate, non-primate Primate Primate * Non-primate
INSERM Vaccine Research Institute/LinKinVax France PanCov (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
* Sun Yat-Sen University China Unnamed)	Protein subunit Sarbeco	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.)