Progress on Next Generation Covid Vaccines (Update 7)

I’ve been reporting on progress of different types of next generation Covid vaccines separately from time to time. With this post, I’m switching to more frequent updates of developments across the next generation board. That includes intranasal and other mucosal vaccines, vaccines targeting more coronaviruses than SARS-CoV-2 – the one that causes Covid-19, as well as vaccines aiming to provide more variant-proof protection against Covid. To catch up on the background, check out the April posts on mucosal vaccines and pancoronavirus vaccines.

Highlights coming in this post: There are positive early clinical trials results for a self-amplifying mRNA vaccine aiming to protect against all SARS-CoV-2 variants, more preclinical results for pancoronavirus vaccines – including an intranasal one – and some information on the US government Project NextGen. Plus, there are now 6 countries that have authorized mucosal Covid vaccines, and there’s some more data from clinical trials.

Contents:

• 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

US Project NextGen

Most of the $5 billion US NextGen money is reportedly earmarked for public-private partnerships through the Biomedical Advanced Research and Development Authority (BARDA), with $300 million for the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). (NIAID is the Institute that was led by Fauci.)

There’s more detail at NIAID here. NIAID is planning to support “existing infrastructure and network sites to implement a structured program evaluating up to 10 next generation COVID-19 vaccines in Phase 1 and Phase 2 clinical trials.” There will be common protocols for the trials, and centralized testing for immune responses. As well as moving some vaccines forward, they aim to “advance science in the field by evaluating how immunologic parameters correlate with protection from infection and disease.”

They define next generation vaccines as ones with better breadth of protection against variants, better durability, and also those that could block transmission/infection. The vaccines have to either already be in clinical trials, or able to be – with US participants – by January 2024. The closing date for developers to notify BARDA of their interest was May 26.

All that narrows down the field a bit. NIAID already supports several next generation Covid vaccine projects – more on their past grants here. Several of the vaccines discussed or listed in this post have had NIAID support, including:

• Sponsoring a trial for the Gritstone “variant-proof” vaccine I mention in the post intro. (There’s more below on results for 2 of the 3 phase 1 trials underway that vaccine below.)
• Support for the pancoronavirus vaccine from the University of California Irvine.
• A grant for developing the intranasal vaccine by CyanVac and their affiliate, Blue Lake Technology – a phase 2 trial was registered in February for that vaccine, though it’s not yet reported to be recruiting.
• The panbetacoronavirus vaccine from Duke University with new preclinical results.
• CalTech’s panbetacoronavirus vaccine, Mosaic-8b – last post I noted that the developers said they faced a hurdle to going into trial: Their vaccine is complex, making manufacture complex, too.

That last example underscores the need for manufacturer commitment if a vaccine is to progress into the phase 3 trial necessary for approval by the US FDA.

I haven’t seen a timetable for when we might expect to hear about which vaccines will get a boost from Project NextGen.

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Mucosal vaccine news

I had missed the news of the authorization of Convidecia Air, CanSino’s inhaled vaccine in Morocco in November 2022 and Indonesia in March 2023. That brought the number of countries using mucosal vaccines to 6. The first 4 were China, India, Iran, and Russia.

In other Convidecia Air news, a study of the impact in the clinic of administering this aerosolized vaccine has been published. The vaccine is used with a nebulizer – it’s inhaled into the lungs through the mouth, in a similar way as some asthma meds are used. The team conducting 2 of the trials of the vaccine took air samples, swabs of the desks and masks of the participants after vaccination, as well as blood samples from the nurses administering the vaccine.

They found a lot of environmental traces of the vaccine soon after vaccination, with some still at 48 hours, and the nurses had very elevated levels of antibodies even though they wore masks while administering the vaccine. The authors recommend using ventilation and ultraviolet radiation to reduce the environmental impact of the vaccine, but say that better solutions to the problem are needed.

In the last month, we’ve seen more clinical data on 2 intranasal vaccines – Mambisa (Cuba) and Patria (Mexico).

Mambisa is an intranasal protein subunit vaccine manufactured by CIGB (Cuba). A phase 2 trial used either it or the manufacturer’s injected vaccine (Abdala) as a booster in people who had previously had Covid. Results were presented at a conference in April, and there was a press report, but only minimal information. (The trial register entry of the trial is here.)

There were 1,041 participants, half of whom had intranasal Mambisa. The trial’s criteria for success were reportedly met. The researchers identified signs of immune response in nasal mucosa of participants who got Mambisa. The press report says that over 90% of participants had showed high levels of immune response, but there’s no data on what this means.

There’s now a journal publication of the phase 1 trial results for the Patria trial, including using an intranasal boost after a first dose by injection, and both doses intranasally. (A preprint had been released in February, but the journal publication reports more information.) The Patria vaccine is manufactured in Mexico by AviMex – a version of a US-developed vaccine that’s available for low and middle income countries to develop without royalties. 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.

It was a small trial, evaluating safety and signs of immune response to 3 different doses. Other than the obvious differences in adverse reactions related to the injection and nasal administration, there wasn’t a major difference in reactions. Systemic immune responses were lower for the group who got no injection. The authors assume that there was a mucosal immunity advantage to nasal administration, but that wasn’t measured. (There’s no clear standard for doing this.) There’s also a trial underway of intranasal booster after previous vaccination with other vaccines.

Meanwhile, recent preclinical results for mucosal vaccines include an intranasal pancoronavirus vaccine, included below.

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Covid-19 “variant-proof” vaccine news

There’s positive new clinical data for a vaccine aiming to protect against all variants of SARS-CoV-2. It’s being developed by Gritstone Bio (USA), with support from NIAID, Coalition for Epidemic Preparedness Innovations (CEPI), and the Gates Foundation. Called CORAL, it’s a project to develop self-amplifying mRNA vaccine.

This type of vaccine includes less actual mRNA per dose – making it cheaper and easier to produce, but can carry more components, and has the ability to multiply and produce antigens for longer – which could theoretically make a vaccine more potent and durable than an mRNA vaccine. (More on the different types of mRNA vaccine here.)

Gritstone Bio presented data on 2 clinical studies at a conference in April:

• A phase 1 trial in the UK, with the GRT-R910 version of their vaccine as a booster in people aged 60 or older. Participants had originally been vaccinated with the AstraZeneca, J&J, Moderna, or Pfizer vaccines, and they received 1 or 2 does of GRT-R910. The developers reported signs of immune response against variants of concern that weren’t incorporated in the vaccine, and these were still strong at 6 months.
• A phase 1 trial in South Africa, with the GRT-R914 version of their vaccine that’s adapted for Beta and Omicron. This trial included people who had no previous Covid vaccine, had previously had Covid, and people living with HIV. People got 1 or 2 doses. Again, signs of broad immune response were still strong at 6 months.

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Pancoronavirus vaccine news

I had previously missed the closest thing we’ve had to a report on a human trial of a pancoronavirus vaccine. The US Army Walter Reed developers (WRAIR) presented some information on their phase 1 trial to WHO. No results were included in the slides published online (dated March 25). However, there is some new detail. For example, now we know the developers have data on primary endpoints for 28 people, most after 2 doses, some with 3 doses. And the endpoints for the trial include signs of immune response to sarbecoviruses, and to SARS-1.

Preclinical results have now been released for an 18th pancoronavirus vaccine. It’s from the University of California Irvine (USA), and it’s a viral vector vaccine. This is another project with NIAID funding. Both are for studies in mice, and both test for protection against variants of SARS-CoV-2 only. The first report is for an injected version of the vaccine, and the second is for intranasal administration.

There was a third report of preclinical studies for the Duke University panbetacoronavirus vaccine, RBD-scNP (USA). In this study, a version of the vaccine incorporating subunits from SARS-CoV-2, MERS, and a bat SARS-related coronavirus protected mice from challenge with 2 variants of SARS-CoV-2 and MERS. However, a version of the vaccine incorporating only SARS-CoV-2 didn’t protect against MERS.

Finally, there’s a journal publication now for a preclinical study previously available as a preprint – for the development of SK Bioscience’s vaccine.

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Addendum 1: Table of mucosal vaccines in clinical trials

* Indicates a new vaccine, or a new entry for a previously listed vaccine, since my last 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). 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.
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 (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.
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 (previously available in preprint). 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) Tetherex (USA) (All records)	Intranasal.	Phase 1.
(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 this 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 Beta	Non-primate	Phase 1 trial (incl. protocol) (Up to 36 participants) Began December 2021. Fully recruited.
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
Pennsylvania State University USA (Unnamed)	Protein subunit All	Non-primate
* Scripps Research Institute USA (Unnamed)	Beta	Protein subunit Non-primate
SK Bioscience/ Uni of Washington/Uni of North Carolina at Chapel Hill South Korea, USA GBP511	Protein subunit Sarbeco	* (previously preprint) Primate, non-primate (testing Covid vaccine GBP510 against other sarbecoviruses)	(More on plans for adapting this vaccine – GBP510 authorized as SKYCovione.)
* 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
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.)