(C) PLOS One This story was originally published by PLOS One and is unaltered. . . . . . . . . . . Trial Results for Longer-Lasting Covid Vaccines and More (Next Generation Update 17) [1] ['Hilda Bastian'] Date: 2024-05-31 This month, there are clinical trial reports for 3 next generation Covid vaccines – including 2 self-amplifying mRNA vaccines that have shown early signs of being longer-lasting than current mRNA vaccines. The third is first full report of a clinical trial of a pancoronavirus vaccine – up to now, we have only seen a press release for trial results of another vaccine in this category. In this update, I’ve also added 18 reports of preclinical studies, including another 2 showing intranasal vaccination reduced transmission among animals sharing the same air. There is also news about developing versions of Covid for running the human challenge trials planned for mucosal vaccines. As usual, I have the news broken down into 3 categories of next-generation Covid vaccines (definitions below). Mucosal vaccine development news Durable or “variant-proof” vaccine news Pancoronavirus vaccine news Addendum 1: List of authorized vaccines (with countries) Addendum 2: Table of mucosal vaccines in clinical trials Addendum 3: Table of pancoronavirus vaccines with results Addendum 4: Definitions of vaccine types Mucosal vaccine news There were no new clinical trials, or trial results, for mucosal vaccines this month. There was news on human challenge trial projects, plus several preclinical studies – including another 2 studies demonstrating reduced transmission among co-housed animals. Human challenge trials news There’s some news on where the MusiCC project is headed. That’s the international project, led by Imperial College London, that aims to test mucosal vaccines in human challenge trials – I wrote about it in March (Update 15). A group from Oxford University reported results of their attempt to develop a version of Covid that would be suitable for this kind of trial. Their phase 1 trial began in 2021, recruiting 36 participants by November 2022. Despite escalating the dose, they weren’t able to infect any of the participants. Their vaccine was based on the original Covid, and by the time of their trial, people had either had Covid or been vaccinated. Imperial College’s successful trial had been earlier, when it was still possible to recruit a group of people in the UK who had not been infected, before vaccines rolled out. In an interview discussing these new results, Christopher Chiu, the lead investigator for MusiCC, said that they are working on a version based on BA.5 Omicron: “Chiu says that his team is exploring the possibility of screening potential participants to identify those with low levels of immune protection against the BA.5 variant and any future challenge strains.” New preclinical results: I’ve added 7 preclinical reports on results for mucosal vaccines to my collection since the last update, including one mucosal vaccine in China that also aims to be variant-proof. Notable studies include: National Cancer Institute (NIH NCI) (USA): This study in hamsters compared a booster of an intranasal protein subunit vaccine with an injection of Moderna’s mRNA vaccine. All the animals had a first injection of Moderna vaccine. A few weeks after their boosters, they were challenged with Covid infection, along with a comparison group of unvaccinated hamsters. Vaccinated hamsters were then individually housed with an unvaccinated one. The cages were sealed, and allowed no contact between the animals except for shared air. The vaccinated hamsters were similarly protected against getting sick with Covid, but those who had the intranasal booster had lower levels of virus in oral swabs. None of the animals the intranasally-boosted hamsters were housed with got infected, whereas 2 out of 3 of the animals housed with Moderna-boosted hamsters got infected. There has been one other preclinical report for this vaccine. University of Guelph (Canada): This study in mice and hamsters tested one or 2 doses of an intranasal viral vector vaccine, based on Newcastle Disease Virus. It appears to be another vaccine based on the Castlevax/Icahn MtSinai vaccine. The vaccine is based on the original SARS-CoV-2, and animals were challenged with Delta and Omicron. The developers concluded that the vaccine provided protection for the 6 months of the study. Israel Institute for Biological Research: This study reports on a mucosal version of BriLife, a VSV-based viral vector vaccine. The injection version is currently in clinical trials (records on this vax). Mice were vaccinated with 2 injections, 2 intranasal doses, or an injection followed by an intranasal dose, followed by a Covid challenge test. Hamsters were vaccinated with an injection followed by an intranasal dose. Those animals and unvaccinated hamsters had a Covid challenge test, and were then co-housed for 24 hours with unvaccinated, unchallenged hamsters, with shared air and limited contact, then tested for infection 3 days later. The developers reported that immunity was greater after intranasal boosters, and continued for the year of the study. Most of the co-housed unvaccinated hamsters showed signs of infection, while there was no detectable virus for the vaccinated hamsters and their co-housed animals. Mucosal Covid vaccine overview 5 mucosal vaccines are currently authorized for use, at least 1 in each of 6 countries. However, none have been authorized by a drug regulatory agency designated stringent, or listed, by WHO. 28 mucosal vaccines have reached clinical trial, although at least one of those has been discontinued. These are tracked in a table below. In addition to the 5 authorized mucosal vaccines, 4 have reached phase 2 trials, and another 2 have reached phase 2/3 trial. US Project NextGen-funded trials in this category: Project 2b (“mini-efficacy”) for the intranasal protein subunit vaccine from Castlevax (planned to start in the last quarter of 2024); Project 2b for the intranasal live attenuated vaccine from Codagenix; and Project 2b for the oral viral vector vaccine from Vaxart. None of these trials has been registered at ClinicalTrials.gov as yet. Back to contents Durable or “variant-proof” vaccine news This month, there were clinical trial results for 2 vaccines in this category, both self-amplifying mRNA vaccines (SAM or samRNA) – including one that is already authorized in Japan. SAM doesn’t just leave a message and disappear, the way current mRNA vaccines do. It makes copies of itself inside our cells – similar to the way a virus works. Theoretically, leaving a blueprint behind enables longer-lasting immunity than mRNA can offer, and there is some evidence that it’s working out for some SAMs. I also added new reports of preclinical research for 5 vaccines in this vaccine. LUNAR-COV19 from Arcturus (USA) – combined results of a phase 1 to 3 trial This vaccine was registered in Japan in November 2023, making it the only next generation Covid vaccine authorized by a drug regulator designated stringent or listed by the World Health Organization. The company has filed for authorization in Europe and is in discussion with the FDA in the US, and it has a partnership for manufacture with Australia’s CSL Seqirus. I have an overview of this vaccine’s clinical trials here, including a summary of the first early results from the phase 3 trial in Vietnam. Later, the developers published 3- and 6-month data. By six months, neutralizing antibodies had fallen off substantially for the BNT-Pfizer vaccine, especially against Omicron strains. For LUNAR-COV19, there was substantially less waning, though there was some. (My summary here). There is an updated version of the vaccine in trials, but the version in this trial is ARCT-154, the one that is authorized in Japan with the name LUNAR-COV19. The trial was an integrated phase 1 to 3 trial, and the new publication pools data from all 3 phases. The efficacy calculations come from the major phase 3 part of the trial, and are the same as for the preprint in my earlier summary. This is efficacy during a Delta wave: Any confirmed Covid, including very mild disease with a single symptom: 56.6% (95% CI: 48.7–63.3). Severe Covid: 95.3% (80.5–98.9), with 2 in the vaccine group and 41 in the placebo group. Death from Covid: 86.5% (-7.4–98.3), with 1 death in the vaccine group and 9 in the placebo group. The publication includes previously unpublished data from other parts of the trial, and safety data is pooled across all parts of the trial. Over 70% of participants had adverse systemic reactions after the first injection, most commonly fatigue. However, the rate of severe reactions was low, apparently less than 5% – I could only find a diagram, not the precise figures for this. The authors report that the 12-month follow-up data from the phase 3 trial are being analyzed. GRT-R918 from Gritstone Bio (USA) – more phase 1 trial results: This is a self-amplifying mRNA vaccine. It is one of the vaccines funded by the US Government’s Project NextGen to run a mini-efficacy, phase 2b trial. The trial had been planned for early 2024, but the company has reported that it has been pushed back to later this year to allow for manufacturing improvements. The vaccine has also received funding from the Coalition for Epidemic Preparedness Innovations (CEPI) and the Gates Foundation. If it makes it through to authorization, then some of this vaccine will be supplied to the international COVAX program. The developers have been running 3 phase 1 trials: in the US, in the UK, and another in South Africa including people living with HIV. Last year, I summarized the previous trial data. It’s too early to know about this vaccine’s efficacy, but what we’ve seen so far included some signs of greater durability than first generation vaccines, and a high rate of short-lived adverse reactions (including chills, fever, and nausea). The new data comes from the trial in South Africa. It began in 2022, and they released 2 posters of early results last year (in April and October). This new poster includes data for 12 months after vaccination for all trial participants, and adds Part D of the trial. There were 341 people altogether in the trial. In part D, there was an Omicron-adapted version of the vaccine (GRT-R918), in 50 adults up to 60 years of age, and 49 who were 60 or older. Some had been previously vaccinated and got only a booster, some had never had a Covid vaccine, and some are living with HIV. Each of the 3 versions of the vaccine used in this trial resulted in increased immune responses to multiple Covid variants in most of the people vaccinated – and those signs of immunity were holding at 12 months. (Records on this vax.) Preclinical studies: I added 6 reports of preclinical studies in this category this month: PRIME-2-CoV (Germany): There were 2 publications for this ORFV-based viral vector vaccine developed at the University of Tübingen, with Speransa Therapeutics. One report was for the original Covid strain version, studied in mice, rats, and rabbits. The other was for a version adapted for the Beta variant, studied in mice and hamsters. That paper reports that a phase 1 clinical trial was successful. That trial has been terminated, noting “business reasons.” Presumably that is because of a decision to go ahead with a different version. The company’s website lists Delta and Omicron versions, with the Delta version apparently approaching a phase 1 trial. Unnamed vax (Canada): This is a protein subunit vaccine, developed by the Vaccine and Infectious Disease Organization (VIDO) at the University of Saskatchewan. The study in hamsters showed signs of immune response against 3 Covid variants. Ad5-US (China): This is an adenovirus-based viral vector vaccine, developed by the Division of Arboviral Vaccines, NIFDC, Beijing. The study in mice compared injections and intranasal doses. Unnamed vax (China): This is a rabies-based viral vector vaccine, developed at Jilin University in Changchun. The study was in mice. Unnamed vax (Singapore, Australia): This is a dendritic cell vaccine, developed at the National University of Singapore and the Monash Biomedicine Discovery Institute. The study was in mice. Durable or “variant-proof” vaccine overview Note: This is a rather vague category, including vaccines that aim to be more durable. I’m not sure how many can be classified as aiming to be “variant-proof”. Authorized vaccine: There is one vaccine in this category that has been authorized by a drug regulatory authority designated by WHO has stringent, or listed – and tested against an mRNA vaccine: LUNAR-COV19 (USA): This self-amplifying mRNA vaccine was authorized in Japan in November 2023. US Project NextGen-funded trials in this category: Phase 1 for TNX-1800 from Tonix (aiming for lifelong immunity); Phase 2b (“mini-efficacy”) for Gritstone Bio (self-amplifying mRNA). Neither of these trials has been registered at ClinicalTrials.gov as yet. Back to contents Pancoronavirus vaccine news Pancoronavirus vaccines aim to provide protection not only from variants of the SARS virus that causes Covid, but also against the next new coronavirus to spread among humans. This month, we got the first full publication of results from a clinical trial of a vaccine in this category, and a preclinical report from another. Phase 1 results for the pancoronavirus vaccine from the US Walter Reed Army Institute of Research (WRAIR) This vaccine is a protein subunit vaccine, based on the original Covid. Participants in this trial in the US were vaccinated back in 2021, and we now have a full report of results. As well as the safety and immunogenicity trial for the vaccine called SpFN/ALFQ, there was a study of what’s called a passive transfer for a challenge test in hamsters – a group were injected with immunoglobulin from vaccinated people’s blood. There were 29 participants in this trial, who were randomly assigned to 2 injections of placebo, or a lower or higher dose of the vaccine. Of those, 9 left the study along the way, including 3 from the placebo group, and half of the 20 people who completed follow-up took up the option of a third injection. None of the people who withdrew from the study reportedly did so because of adverse reactions. The developers had intended to enrol more participants, but it became too difficult to recruit people who were unvaccinated and had not had Covid. People in the trial showed signs of immune response to several Covid variants, including Delta and Omicron, as well as varying degrees of response for a range of other sarbecoviruses (the coronavirus subgroup that includes both Covid and the original SARS). Signs of immune response were stronger or coronaviruses more closely related to Covid, and there were no signs of immune response to MERS. Almost everyone had systemic adverse reactions to the vaccine (88%), and 1 person had a severe fever that resolved within a few days (4%). The most common systemic reactions were fatigue and/or muscle aches. In the passive transfer study, hamsters were injected with immunoglobulin (IgG) from trial participants who had 3 injections of the vaccine. Those hamsters were then given the original SARS, along with some injected with saline or a control IgG. Those injected with the trial participants’ immunoglobulin had lower rates of lung inflammation than the others. There was no mention of proceeding to phase 2 with this particular version of the vaccine. WRAIR is now part of a collaboration involving the Sheba research institute in Israel, the NIH Vaccine Research Center, and Sanofi. There’s been no recent news on that. Mosaic 8b (CalTech, USA and Oxford and Cambridge Universities) preclinical study report This vaccine is based on proteins from 8 coronaviruses, and the developers have previously reported that the complexity of the vaccine would make it difficult to manufacture. In this latest study in mice, the developers reported that they had simplified the vaccine by fusing the proteins into 2 sets of 4, called a Quartet Nanocage design. The vaccine still resulted in signs of immune response to a range of sarbecoviruses, including Covid variants and the original SARS. This included testing for viruses other than the 8 on which the vaccine is based. In a press release, the developers reported that a first-in-human clinical trial is planned to start early next year. Even with the simplified version, the vaccine remains complicated. No manufacturer was reported to be attached to the project. The group also updated a preprint from earlier this year. (Records on this vax.) Pancoronavirus vaccine overview A table below this post keeps track of vaccines I’ve added to this category so far that have publicly available preclinical results. There are 5 of these vaccines in phase 1 clinical trials, with some results for 2 of them marked *: DIOSynVax (Cambridge University spin-off, UK) – mRNA. INSERM/LinkInVax (France) – protein subunit. Osivax (France) – protein subunit. * VBI Vaccines (Canada) – eVLP. * Walter Reed Army Institute of Research (WRAIR, USA) – protein subunit. Back to contents Addendum 1: List of authorized next generation Covid vaccines (with countries) There are now 7 next-generation Covid vaccines authorized in 7 countries. Only one has been authorized by a drug regulatory agency designated stringent, or listed, by WHO – it’s in bold. I’ve listed the vaccines in 2 categories, in order of date of first authorization. Mucosal: Razi-Cov Pars (Iran), intranasal protein subunit vaccine: Iran (October 2021). Sputnik (Russia), intranasal viral vector vaccine: Russia (April 2022). Convidecia (China), inhaled viral vector vaccine: China (September 2022), Morocco (November 2022), Indonesia (March 2023). iNCOVACC (USA/India), intranasal viral vector vaccine: India (September 2022). Pneucolin (China), intranasal viral vector vaccine: China (December 2022). Self-amplifying mRNA: Gemcovac (India): India (June 2022). LUNAR-COV19 (USA): Japan (November 2023). Back to contents Addendum 2: Table of mucosal vaccines in clinical trials No new entries 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. Back to contents Addendum 3: Pancoronavirus vaccines with preclinical results * Indicates new entry since previous update post. Back to contents Addendum 4: 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. I include vaccines that aim for greater durability in this group. 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). Back to contents You can keep up with my work at my newsletter, Living With Evidence. And I’m active on Mastodon: @hildabast@mastodon.online ~~~~ 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: 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 cartoon is my own (CC BY-NC-ND license). (More cartoons at Statistically Funny.) 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