This Month’s Progress in Next Generation Covid Vaccines (Update 8)

Next generation vaccines are already varying from each other a lot, just as the first generation did. However, there are several ways that some next generation vaccines could turn out to be more effective than the originals, including potentially staying effective for longer. The vaccines could hold their own better against the current coronavirus’ variants, be protective against future coronaviruses, and/or protect against getting infected as well as against serious disease. This month, there’s a lot of progress to report in all 3 of those categories, including some more data from clinical trials.

Highlights in clinical trials in the last month include results of a phase 3 trial of the inhaled vaccine from China’s CanSino. A couple of vaccines have also reported that early phase 1 trials have had reassuring safety results and are expanding. One is the Tetherex intranasal vaccine, initially developed by the Mayo Clinic – it’s now testing an inhaled version as well. The other is the needle-free mRNA pancoronavirus vaccine from Cambridge University spin-off, Diosynvax – that trial is now recruiting more people in Cambridge. And there’s a publication of some phase 1 results for the Gritstone Bio vaccine aiming to be “variant-proof”.

This post also discusses several preclinical studies. Highlights here include the protein subunit pancoronavirus from the Inserm Vaccine Research Institute in France. In a conference presentation earlier this year they reported that in mice, their vaccine induced more long-term immune memory cells than the Pfizer Covid vaccine could. And another vaccine that’s showed better signs of mucosal immunity in preclinical studies than the Pfizer vaccine has been modified. It’s a live vaccine developed in Germany at the Freie Universität of Berlin. The live virus has been modified to reduce the risk of submission. Those developers are working with a Swiss pharmaceutical manufacturer.

In an article in The New York Times, Mueller, Weiland, and Zimmer report that more than 70 companies responded to the US Government’s Project NextGen call. (There’s background on this in my previous update.) Spokespeople said a “handful” of grants will be awarded in the next few months, and “a dozen or more” by early 2024.

However, the article includes several people dampening expectations about what’s possible, and pessimistic takes about lack of resources from spokespeople from several small companies. It’s hard to know if that picture would look different if there had also been spokespeople from groups expecting to receive funding, and for whom there are prospects for running phase 3 trials after Project NextGen support is over. I think non-US-centric perspectives might be different, too – especially where manufacturers can be fairly confident that governments would invest considerable resources in purchasing improved vaccines. For most of us, better vaccines than we’ve got access to already aren’t just around the corner – but there are quite a few vaccine candidates definitely worth watching with fingers crossed. It’s been just 4 weeks since my last update post, and there’s a lot for you to dig into from that short time.

Contents:

• 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

Results for the largest phase 3 trial of aerosolized Convidecia as a booster after inactivated vaccine has been published – with over 10,000 people in China. That’s the viral vector vaccine from CanSino, and it was compared to a booster of inactivated vaccines (some of the least effective Covid vaccines). Adverse events were relatively low, with a rate of 13% of recipients in the first 28 days. People who got the inhaled vaccine had higher levels of neutralizing antibodies as those who received a third inactivated vaccine shot. Signs of immune response in saliva were also measured. It wasn’t detectable in most people before the booster, and was much higher in the inhaled vaccine group afterwards – but by 3 months, there was no difference again. However, neutralizing antibodies were still higher after the inhaled vaccine at a year.

There’s progress on the intranasal viral vector vaccine that US pharmaceutical company Tetherex licensed from the Mayo Clinic. It’s called SC-Ad6-1. A phase 1 trial for this vaccine had started in Australia in June 2022. In September, Tetherex announced they’d started a spin-off company called Moat Biotechnology to further develop the vaccine. This month, Moat Bio reported in a press release that the majority of people in the trial who had the vaccine had a systemic as well as mucosal response. The trial has now been expanded from 130 to 190 people, with the additional people testing an inhaled version of the vaccine.

In other news, the developers of the Oragenics intranasal Covid vaccine received funding to develop it as a pancoronavirus vaccine – more on that in the pancoronavirus section below. It’s in the preclinical development phase.

In the last month, I’ve added 5 preclinical studies for mucosal Covid vaccines to my database, all for vaccines that aren’t in clinical trials. They are:

• A challenge study in hamsters for an intranasal pediatric viral vector vaccine, based on parainfluenza, developed by the NIH’s NIAID. With positive results, including for Omicron, the study authors report that the vaccine will be further developed to try to protect infants from both Covid and parainfluenza type 3.
• Results in mice for a vaccine called ISR52 being developed by Swedish company ISR Vaccine AB, with academic partners. It’s a subunit vaccine in powder form, for intranasal use.
• Another subunit vaccine that’s being developed at Yonsei University in South Korea. The researchers published results in mice for a sublingual version of the vaccine – it’s applied via a dissolving patch.
• Also from South Korea, this time from the Korea Advanced Institute of Science and Technology, come results in mice for an intranasal viral vector vaccine called Ad5-S.Mod.
• Another study in hamsters comes from researchers at the Freie Universität in Berlin, working with a manufacturing company from Switzerland, RocketVax. It’s the fifth clinical research report in my collection for this vaccine, called sCPD9. It’s a live intranasal vaccine that the researchers concluded offered greater mucosal responses than the mRNA vaccine from BioNTech/Pfizer. However, there was some transmission between animals. In this latest study, they modified the vaccine by removing some of the SARS-CoV-2 protein. There was no transmission between cohoused animals, and it was tested for safety in immunosuppressed mice as well. A press release from Rocketvax says that clinical trials for this vaccine are coming, though it doesn’t say when.

Finally, the Dutch government is privatizing its vaccine manufacturer, Intravacc. It’s not clear what impact this will have on the company’s intranasal protein subunit vaccine – it’s in a phase 1 clinical trial.

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Covid-19 “variant-proof” vaccine news

In the last update, I included some brief results of 2 phase 1 trials of Gritstone Bio’s self-amplifying mRNA vaccine from conference presentations, with a brief discussion of this vaccine. This US company has support from NIAID and others, and if it is eventually successful, some of the vaccine will be supplied to the COVAX program. This month, results for one of them have been published.

It’s a trial of using the Gritstone vax as a booster in people aged 60 years or older in the UK, who had previously been vaccinated with the AstraZeneca vaccine (a viral vector vaccine, that was not among the most effective Covid vaccines). The trial began in September 2021, originally planning to include 120 people. Later, it was dropped to 40, with some people previously vaxed with mRNA or J&J vaccines as well. The publication reports that 54 people had been assessed for eligibility. This report covers 17 people who had AstraZeneca first.

All of the 17 got a single shot of the Gritstone (either 10 µg or 30 µg), and they had the option of getting a second booster 20 weeks later: 10 chose to have it the second shot. Adverse events were common, but not severe at the lower dose – some headaches were severe for people getting the higher dose. More people reported adverse events after the second shot.

As the company had reported in the conference poster in my last post, antibodies for the variants they tested – Beta, Delta, and Omicron – increased, and were maintained at 6 months with only a small slump. That was so for people who had only a single dose as well, although that’s a small number of people.

What they didn’t report in the poster, though, was that when Omicron emerged, 8 of the 17 people were infected. It’s not clear how many were infected before a second dose, or before the time when a vaccine could be considered to have taken effect. They only reported the median time since dosing (which wasn’t defined). That was 3.6 months, with a range from 12 days to 5.2 months. Although their age put these people at high risk for severe disease, none became so severely ill that they were hospitalized.

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Pancoronavirus vaccine news

There was news this month for one of the pancoronavirus vaccine candidates that’s in a phase 1 trial. It’s the needle-free mRNA vaccine from Cambridge University spin-off company, Diosynvax. Apparently the developers are happy with the safety results, and have expanded the trial to Cambridge for the dosage-setting stage – it was originally only recruiting in Southampton. Although this expansion was announced, it’s not reflected in the current registry entry for this vaccine. That entry reports that the trial was already fully recruited, and doesn’t note the Cambridge site.

I’ve sent off some queries for more information. I haven’t get direct answers yet, but I was sent a copy of the patient information sheet, which was helpful. That confirmed that it’s still a phase 1 trial, and the dosage strengths being tested are the same as those in the trial protocol.

In other news, as I mentioned above, the Oragenics intranasal vaccine is now being developed as a pancoronavirus vaccine (type unspecified). Canadian funding for that project was announced this month. Oragenics is a US company, collaborating with Inspirevax and the National Research Council of Canada on this development. The vaccine is a protein subunit vaccine in the preclinical phase. (You can see their previous publications in the table below.)

I’ve also added a pair of previous preclinical studies I’d missed – one publication from 2021 and a conference poster from February this year. Both are for the vaccine being developed by the Inserm Vaccine Research Institute (France). In the conference poster, the developers report that they compared their protein subunit vaccine (CD40.CoV2) with the BNT/Pfizer mRNA vaccine in humanized mice (mice with grafts). Their hypothesis was that their vaccine would be able to better induce a type of long-term memory cells in the immune system (CD8+ Tscm cells) than the first generation Covid vaccine. They report that their vaccine was able to induce more of 2 types of these long-memory cells (S- and N-specific) than the mRNA vaccine.

Finally, VBI Vaccines has undergone major cutbacks. It’s not clear what impact this will have on the company’s pancoronavirus vaccine, which is in a phase 1 clinical trial.

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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 (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) 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)
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.)
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.)