Front-Runners in the Race for Variant-Proof and All-Coronavirus Vaccines

SARS-CoV-2 – the coronavirus that causes Covid – is the third from its virus family to cause devastating pandemics or outbreaks in the last 20 years. First, there was the original SARS in 2002, and then MERS in 2012. As Fauci and others stress, even worse coronaviruses could spill over to humans, and it’s a feature of these viruses that they allow re-infections. So even though it’s a major scientific challenge, they wrote, we urgently need pan-coronavirus vaccine – that’s vax against all coronaviruses, or the subgroup these 3 viruses came from.

WHO’s chief scientist, Soumya Swaminathan, reckoned in April 2022 that there’ll be one within 2 years. With a few coming out of phase 1 clinical trials now, it’s possible that next year a vaccine – or even more than one – could show that it could at least hold up to new Covid variants. Some may even tackle the other major challenge at the same time: effective mucosal protection to reduce infection as well as disease.

With 2019’s SARS-CoV-2 still mutating and dangerous, vaccine developers are trying to pick it off at multiple levels:

• Adapting existing vaccines to an individual new variant, sometimes combining these versions (multivalent vaccines);
• Developing a version that’s intended to be variant-proof;
• Aiming for a vaccine that can protect against either the “subgroup” the 2 SARS viruses came from (the sarbecovirus subgenus) or the next level up (the genus, betacoronavirus, which includes MERS);
• Targeting the whole coronavirus family.

I wrote a post about the first of those levels – adapting vaccines for variants – in February 2022. This post is about the vaccine development programs aiming for the next levels. It’s a bit complicated, though, even though those categories sound like clearcut distinctions. A vaccine targeted at a particular variant can still provide a lot of protection against other variants – and perhaps even against other coronaviruses – without being designed to. For example, a study in mice in June 2021 found a SARS-CoV-1 vaccine offered some protection against SARS-CoV-2. So a vaccine adding variant targets one at a time might end up getting close to a vaccine being described as “variant-proof”. And a development program with the long goal of very wide protection may have incremental variant-specific steps along the way.

Before I map out the field and single out some current front-runners, there’s a few things to keep in mind. This is a race that’s only partly run in public, so the picture can change quickly: break-out candidates can shoot to the lead, sometimes apparently out of the blue. Front-runners can be waylaid by glitches on the development or regulatory path, too – or by unexpected adverse effects. And our view of what’s happening can be clouded by developers’ wishful thinking and marketing hype. This is also a race for the cash needed to run major studies and advance government vaccine contracts, and commercial advantage.

In this post, I concentrate on progress measured by published results and clinical trials. Elie Dolgin reported that there are dozens of candidates in the works and lists 8 (plus Moderna’s effort to get one for common cold coronaviruses). I’ve seen around 20, but I don’t know of a comprehensive list and only keep track of ones with results. As well as Dolgin’s list and my own results-tracking collection, I looked at the broad-protection program run by CEPI, the international pandemic preparedness organization supported by governments and others, and the papers from a WHO consultation.

Side-note: 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.

I found 16 vaccines that have any results (almost all preclinical) and/or are in clinical trials. They’re detailed in a table at the bottom of this post. Of those, 4 seem to be further along because they’re in clinical trials, and another is close to starting. At this early stage, that might not be the best guide if any of the programs suffer from shortcuts in the preclinical stage. I’ve also added another 3 developers to that front-runner group. The first is BioNTech-Pfizer, because their experience with running Covid vaccine trials and satisfying regulators’ expectations is an advantage that could see them overtake others in the later stages if they have effective vaccines – which is just what they did with their original Covid vaccine. The other 2 – Caltech and Duke University – have clinical trials in sight, and have reported preclinical studies involving multiple species and challenge studies (exposure to virus to try to infect the animals) – that strengthens confidence in the findings.

I didn’t include another developer with a vaccine already in use that is embarking on a pan-sarbecovirus vaccine, because they are just starting out. That’s SK Bioscience, manufacturers of SKYCovione (GBP510), a protein subunit vaccine which is currently authorized in South Korea. (Records in my collection for that vaccine here.)

The group of 8 current front-runners includes:

• 2 mRNA vaccines, 2 ferritin nanoparticle vaccines, an adenoviral vector vaccine, a protein subunit vaccine, a DNA vaccine, and a mosaic nanoparticle vaccine;
• 3 vaccines that already have results from phase 1 clinical trials, and another that’s likely to soon – they’re marked * below;
• 2 already being tested as mucosal vaccines (intranasal and an oral vax), which have the potential to protect against infection;
• 5 vaccines developed in the US, 2 in Europe, and 1 in the Middle East.

If you’re only going to read about a few, check out the ones marked * below. The whole 8 are listed in alphabetical order by developers, with a link to my summary about each of them. Each begins with a description of the vaccine and how many results and trials it has, followed by descriptions of each of those – but you can get the picture by hopping from one “intro” to the next:

• BioNTech-Pfizer: mRNA vaccine, aiming to be “pan-coronavirus”.
• Caltech: mosaic nanoparticle vaccine, aiming to be pan-betacoronavirus.
• * DIOSynvax: DNA vaccine using jet of air rather than needle injection and transferable to other platforms (eg mRNA or adenoviral vector vaxes), aiming to be pan-sarbecovirus.
• Duke University: ferritin nanoparticle vaccine, aiming to be pan-sarbecovirus.
• * Gritstone Bio: self-amplifying mRNA vaccine (and an adenoviral vector version), aiming to be “pan-coronavirus”.
• * ImmunityBio: adenoviral vector vaccine, aiming to be “variant-proof”.
• MigVax: protein subunit vaccine (oral), aiming to be pan-betacoronavirus.
• * Walter Reed Army Institute of Research: ferritin nanoparticle vaccine, aiming to be pan-betacoronavirus.

BioNTech-Pfizer:

No published preclinical results, clinical trial pending

This mRNA development team reported to BioNTech investors that they expect to go into clinical trials with a T-cell enhancing pan-coronavirus vaccines this year (slide 66) – but they haven’t released any further details or preclinical results. They’re expecting to have “multiple product launches” for next-generation or variant-specific Covid vaccines in the next 3-5 years, and 5-10 applications to regulators for approval for clinical trials or for use each year (slide 12).

Caltech:

Results in primates and non-primates

This vaccine from the California Institute of Technology (Caltech) is based on mosaic nanoparticle technology developed at Oxford University. It’s based on a fragment of the spike protein (RBD) from 8 different coronaviruses in the betacoronavirus genus – hence the vaccine’s name, Mosaic-8b. Because this RBD is shared by betacoronaviruses generally, this vaccine is aiming to be pan-betacoronavirus. (Description here.)

The group has published results of a study in mice using a mosaic of 4 or 8 types, and found the blood of vaccinated mice could recognize mis-matched strains of the virus. The types included SARS-CoV-2 and bat and pangolin coronaviruses. Their latest paper reports on studies using Mosaic-8b and comparing it to a SARS-CoV-2-only vax in mice and macaques. As well as testing blood, the vaccinated animals were challenged with original SARS and SARS-CoV-2. And even though the original SARS wasn’t one of the 8, the vaccine provided cross-protection.

Before they go to phase 1 trial, they’ll be completing another preclinical study with animals that have been vaccinated with other Covid vaccines. That’s because the people in the clinical trial will have been vaccinated or have had Covid. More from the developers here.

DioSynvax:

Results in non-primates, a fully recruited phase 1 trial

DioSynvax is a for-profit spin-off from the University of Cambridge. The vaccine is called DIOS-CoVax, and it’s a DNA vaccine using synthetic antigens. It’s injected using a spring-powered jet of air rather than a needle. It’s designed to be a pan-sarbecovirus vaccine, though CEPI describes it as pan-betacoronavirus.

This vaccine has been studied in mice, guinea pigs, and rabbits. The mice were first vaccinated with the AstraZeneca vaccine, using DIOS-CoVax as a booster. They were challenged with original SARS-CoV-2 and Delta. In the various experiments, animals were tested for responses to original SARS, 2 bat coronaviruses, and SARS-CoV-2 – original, Beta, Gamma, Delta, and apparently Omicron.

A phase 1 clinical trial to test safety of escalating doses began in December 2021, and is fully recruited (for 36 participants, if the trial ended up continuing to the highest dose to test). It’s a booster trial – all the participants had to have had 2 doses of another Covid vaccine at least 3 months previously, and never infected with a SARS virus or MERS.

The participants would have 2 doses of DIOS-CoVax, 28 days apart. They will be assessing signs of immune response 4 weeks after the second dose. Assuming all goes well, the results will be used to determine what dose is used for the phase 2 trial.

Note: Sources here include the clinical trial’s protocol, downloadable from the trial register entry, and a slide presentation to WHO.

Duke University:

Results in primates and non-primates

This vaccine was developed by the Duke Human Vaccine Institute (DHVI). It’s a ferritin nanoparticle vaccine – a fragment of the SARS-CoV-2 virus (RBD) is attached to the protein, ferritin. And it’s boosted with 2 adjuvants, 3M-052 and alum. The vaccine is called RBD–scNP.

The first report of preclinical work for this vaccine was published last year. Macaques were immunized with RBD-scNP only, or as a booster after mRNA vaccination. Their blood showed signs of immune response to original SARS, SARS-CoV-2 and 4 variants, plus 2 bat coronaviruses. The animals were also challenged with SARS-CoV-2.

A second report was released early this year. This time the blood was tested for signs of response to against 8 variants of SARS-CoV-2, including Omicron. As well, immunized macaques were challenged with original SARS-CoV-2 as well as Beta and Delta. And mice were challenged with Beta and 2 other sarbecoviruses.

The developers at Duke expect to start a clinical trial next year. They’re one of the vaccines getting NIH funding, but I haven’t seen it linked to a drug manufacturer yet.

Gritstone Bio:

Results in primates and non-primates, large phase 1 trial recruiting

This is a self-amplifying mRNA vaccine, called GRT-R910. Its design targets antigens in both SARS viruses. The vaccine can also be carried in an adenoviral vaccine, and they are testing that as well.

The developers have published results using GRT-R910 in different dosages as a 2-dose course, or as a second dose after their own adenoviral Covid vaccine, in mice and macaques. They concluded signs of immune response in blood were higher than had been reported for first-generation mRNA Covid vaccines. There was also a SARS-CoV-2 challenge in the primates. Immune responses to other variants or coronaviruses weren’t tested, though.

Those 2 vaccines – GRT-R910 and their adenoviral vector vaccine – are being tested in a phase 1 clinical trial run by the NIH (NIAID), for 135 participants. There are 2 versions of each of those vaccines in the trial – one version has additional SARS-CoV-2 antigen parts (T-cell epitopes). They are being tested as 2-dose courses, and as vaccine combinations – including as a booster in people who had the J&J Covid vaccine. Outcomes for this trial include signs of immune response to variants. That trial began in March 2021.

In September last year, Gritstone began another phase 1 trial, in the UK. Initially for 20 participants aged 60 or older, the trial is testing GRT-R910 with the T-cell epitopes, in 2 dosages, as a booster in people who had previously been vaccinated with the AstraZeneca Covid vaccine. The trial began with 10 people getting the low dose. In January this year, Gritstone reported in a press release that immune responses for them had also been higher than those reported for first-generation mRNA vaccines, so they expanded the trial to 120 participants.

In February this year, the developers also started a 340-participant phase 1 trial of versions of the vaccine adapted for Beta and Omicron.

ImmunityBio:

Results in primates and non-primates, 2 small phase 1 trials fully recruited – some results for one – and 1 small phase 1 trial still recruiting

The ImmunityBio Covid vaccine is based on a human adenovirus 5 vector (Ad5), with some parts deleted (genes encoding several proteins). This is meant to bypass any existing immunity to the adenovirus. The vaccine, AdS+ N, is a bivalent vaccine, that’s dual antigen – it targets the SARS-CoV-2 spike, as other vaccines do, and another protein (the viral nucleocapsid protein). That’s the reason the developers believe it will be more variant-proof and durable than first-generation Covid vaccines. They are also testing mucosal versions – both oral and intranasal – which might help protect against infection.

The developers first publication reports on results of mice being vaccinated with 4 versions of vaccine, in injected, oral, or intranasal form: one made with standard SARS-CoV-2 protein, one with modified spike (S-Fusion), one with the second protein and enhanced T-cell stimulation (N-ETSD), and a bivalent version (S-Fusion + N, called AdS+N for short). They concluded the bivalent version was superior.

Their second publication reports on vaccinating macaques with a subcutaneous injection of AdS+N, then 2 oral doses, or 2 injections and a single oral dose. The primates were challenged with original SARS-CoV-2.

A third report includes 2 injections of AdS+N and/or a self-amplifying mRNA vaccine they developed (called SASA S) in mice. SASA S is based on original SARS-CoV-2 as well as the D614G mutation. They tested for immune responses in the blood to original SARS-CoV-2, Beta, Delta, and Omicron. SASA S, alone or in combination with AdS+N, had better results, including similar responses to all the strains. However, 2 doses of AdS+N did not always reach an adequate response, and although response was good when it was used as a second dose after SASA S for other strains, response against Omicron was weaker by one measure. On the other hand, the “N” in AdS+N broadened responses that the developers believe could be valuable for future variants. Overall, the developers concluded that combination vaccination (heterologous) most broadens potential responses.

The June 2021 preprint for phase 1 clinical trial results includes an analysis of immune responses to variants – including Alpha, Beta, and Gamma. The trial was done in the US. (Delta didn’t become dominant there till July.) The preprint focuses on T-cell results in a high dose group, rather than a full report of the trial. The whole trial was for 34 participants in 6 groups, getting different dosages, in 2 subcutaneous injections, or an injection followed by an oral dose, 3 weeks apart. The developers concluded that the vaccine could potentially be a universal booster.

That trial began in October 2020 in the US. Another 2 phase 1 trials started in early 2021: a trial of different dosages and combinations of injection and oral AdS+N for 26 people in the US, and a trial of different dosages for 35 people in South Africa. The company announced in July 2021 that they had regulator approval in South Africa to start a phase 1/2/3 trial of AdS+N as a boost for healthcare workers who had the J&J vax in South Africa’s Sisonke trial – no further news since then.

ImmunityBio is also part of a consortium developing self-amplifying mRNA vaccine against Covid, but it’s not clear that this is intended to be variant-proof. There is a preprint of preclinical results, and a phase 1/2 trial for self-amplifying mRNA vaccines began in May 2022.

MigVax:

Results in non-primates, phase 1 trial pending

This oral vaccine is a protein subunit vaccine, called MigVax-101. MigVax-101 is based on the developers’ vaccine developed to prevent avian IBV (Infectious Bronchitis Virus) in chickens. IBV is caused by a coronavirus. MigVax plans to build on this and develop another vaccine that could protect against a range of betacoronaviruses.

The developers have published the results of studies in mice and rats. The mice had 3 MigVax doses, testing a variety of dosages. The vaccine was tested as a single or 2-dose booster in Covid-immunized rats (using a different injected experimental vaccine before the oral MigVax). The rats were tested for responses to SARS-CoV-2, but not variants.

A phase 1 trial is expected to start soon.

Walter Reed Army Institute of Research:

Results in primates and non-primates, small phase 1 trial with a public comment about pending results

This vaccine is being developed by the US Army (WRAIR), and it’s called SpFN. As well as WRAIR’s own work on vaccines, Baylor College transferred the tech for their experimental vaccines against original SARS and MERS to them. WRAIR now has a pharmaceutical manufacturing partner for the SpFN vax, but they haven’t announced which company it is.

Like the vaccine from Duke University, this one is a ferritin nanoparticle vaccine – a fragment of the SARS-CoV-2 virus (RBD) is attached to the protein, ferritin. It also has an adjuvant (AFLQ), produced by the Army, too, with saponin – the same type of ingredient in Shringrix and the Novavax Covid vaccine. However, the disease-specific part of the vaccine is only based on the original SARS-CoV-2.

This is one of the vaccines that got off to the earliest start. Results of the phase 1 trial for this vaccine are expected soon, and one of the developers has said the results are positive. They are also running analyses for signs of immune response to Omicron, which wasn’t on the horizon when the trial started. The trial was already registered early in 2021, but the developers say that recruiting even a small number of people who had neither been Covid-vaccinated or been infected was very slow-going – they needed 29. A trial of the vax as a booster is being planned.

In the meantime, they have published 5 papers on their preclinical studies – 3 in mice or hamsters, and 2 in primates (2 species of macaques):

• A study in hamsters included challenging them with the Alpha and Beta variants. The hamsters had been vaccinated with either 1 or 2 doses of SpFN, in high or low dosage.
• They also compared 2 versions of the vaccine, with AFLQ or Alhydrogel as the adjuvant, in a study with mice. The outcomes studied were immune responses. They concluded AFLQ had better outcomes, and that the vaccine elicited a response that could be cross-reactive for original SARS.
• In another study in mice, the developers compared 4 versions of ferritin nanoparticle vaccines, including SpFN and versions where the nanoparticles were engineered to target different parts of SARS-CoV-2. One of them was based on the design of an earlier experimental MERS vaccine. They studied the signs of immune responses, and found signs of response to both SARS-CoVs. Next, they did challenge experiments with the original version of SARS-CoV-2 for mice vaccinated with SpFN or another vaccine (RFN). Although SpFN is their primary vaccine candidate, they also continued work on RFN. (You can see that in the table at the end of this post.)
• A large study in rhesus macaques (32 animals) compared high and low SpFN doses and placebo. Immune responses after 1 or 2 doses 28 days apart were measured, including signs of neutralizing Alpha, Beta, Gamma, and Delta, and original SARS. Then they did a challenge study, with the original SARS-CoV-2. In the discussion section of this paper, they have 3 hyptheses as to why this vaccine works across variants and types of SARS: the reaction is so strong it overcomes the differences, it’s because of nanoparticle features, (and/)or it’s the AFLQ adjuvant.
• In a study in cynomolgus macaques, the developers compared SpFN with AFLQ and SpFN using a conventional adjuvant (aluminum hydroxide). They analyzed immune response to original SARS and original SARS-CoV-2, as well as Beta, Gamma, and Delta variants, and did a challenge study with original SARS-CoV-2. Again, response was better with AFLQ.

Addendum: Vaccines aiming for broad Covid or Coronavirus immunity with results and/or in clinical trial

Developer Country Vaccine name	Preclinical results	Registered clinical trials	Trial status
Caltech USA Mosaic-8b	Non-primate Primate, non-primate		Preclinical studies including animals previously vaccinated with other vaxes planned before a phase 1 trial.
Codiak USA exoVACC Pan Beta Coronavirus	Article on development Non-primate (conference slides) Non-primate (conference slides)
DIOSynvax UK DIOS-CoVax/ pEVAC-PS	Non-primate	Phase 1 trial (incl. protocol) (Up to 36 participants)	Began December 2021. Fully recruited.
Duke University USA RBD–scNP	Primate Primate, non-primate
Gritstone Bio USA GRT-R910 &c	Primate, non-primate	Phase 1 trial (135 participants)	Began March 2021.
		Phase 1 trial (Booster for 20 participants, age 60+ – expanded to 120)	Began September 2021 (UK). Efficacy readout for first 10 participants in January 2022, announcing expansion to 120 participants.
		Phase 1 trial – Beta- & Omicron-adapted versions (340 participants)	Began February 2022.
ImmunityBio USA AdS+N	Non-primate Non-primate (incl SASA S) Primate	Phase 1 trial (34 participants)	Partial results for high dose group. (Includes injected and oral versions.) Began October 2020. Fully recruited.
		Phase 1 trial (26 participants)	Began February 2021. Fully recruited.
		Phase 1 trial (35 participants)	Began March 2021.
ImmunityBio USA SASA S	Non-primate (incl AdS+N)
INSERM Vaccine Research Institute France CD40.CoV2	Non-primate
Mawlan Bhashani Science Technology University Bangladesh (Unnamed)	Non-primate
MigVax Israel MigVax-101	Non-primate		Pending. (Oral vaccine.)
Pennsylvania State University USA (Unnamed)	Non-primate
Sorrento Therapeutics USA (Unnamed)	Non-primate Non-primate
VBI Vaccines USA VBI-2901	Non-primate Non-primate (Press release)		Planned to start in northern hemisphere summer, 2022. (Further background info.)
Walter Reed Army Institute of Research USA SpFN 1B-06-PL	Non-primate Non-primate Non-primate (incl RFN) Primate Primate	Phase 1 trial (29 participants)	Began April 2021. Results expected soon (described as “positive”).
Walter Reed Army Institute of Research USA RFN	Non-primate (incl SpFN) Primate
Yale University USA (Unnamed)	Non-primate Non-primate

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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 

Correction [July 10 and 11]: In the first version of this post, I had mistakenly assumed that MigVax had partnered with another company which had already started a clinical trial of its candidate. I also removed a statement about the vaccine’s design – I’d interpreted a sentence on the company’s website incorrectly – and reference to a challenge study. I added the sentence with a reference to CEPI’s support for them to develop this, and a further vaccine. I’m grateful to Itamar Shalit, a scientific advisor to MigVax, for pointing out my errors.

Update [July 11]: In the first versions of this post, I included brief details of the preclinical studies of the DIOSynvax vaccine, but I hadn’t found a full report. I had however overlooked a preprint at Research Square, and I’m grateful to Simon Frost for pointing it out.

Correction [July 18]: I’m grateful to Alan Jenkins for pointing out an unfinished sentence, which I corrected.

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.

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.)