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A Major First Next Generation Covid Vaccine: Could There Be More in 2024? (Update 13) [1]
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Date: 2024-01-11
A next generation vaccine has been authorized by a major drug regulator for the first time. It’s based on a next generation mRNA, called self-amplifying messenger RNA (SAM, or samRNA). 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. There’s a small amount of evidence showing immune effects of this new vaccine from Arcturus Therapeutics are durable to at least 12 months. Called LUNAR-COV19, it was authorized in Japan late last year.
In this update, I’m starting with vaccine rollout – where else this new vaccine might be authorized this year, and which vaccine might be next. After that, I have recent results broken down into 3 categories of next-generation Covid vaccines (definitions below). The trials for LUNAR-19 are in the “durable” category below, including a recent small head-to-head trial between the LUNAR-COV19 and Pfizer vaccines.
Rollout overview
Mucosal vaccine 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
Rollout overview
The self-amplifying mRNA (SAM) vaccine from this post’s introduction is a vaccine developed by Arcuturus Biopharmaceuticals in the US. It was authorized by Japan in November 2023, making it the first next generation vaccine to get the nod from a drug regulatory agency designated stringent or listed by WHO.
The company has filed an application for authorization in Europe. Arcturus also has a licensing partnership with Australia’s global biotech, CSL Seqiris. CSL Seqiris reports that they are seeking authorizations, but not in which countries. They have a new facility in Boston which will manufacture the vaccine. CSL Seqiris is also building an mRNA facility in Melbourne, though that won’t be operational soon. Arcturus reported that there had been discussions on the design of its phase 3 booster trial with the US FDA and the regulatory authorities for Europe and the UK.
Another 6 Covid vaccines have been authorized in 6 countries, and I’ve listed them below this post, including where they were authorized and when.
One of them is the first SAM authorized, Gemcovac. Like Arcturus’ LUNAR-COV19 vaccine, it was developed by a US company (HDT Bio). They licensed it to a company in India, Gennova in India. It was authorized in India in June 2022 in a trial run by Gennova comparing it with the Oxford/AstraZeneca vaccine. I pointed out some limitations of that evidence here.
The 5 other authorized vaccines are mucosal vaccines – either inhaled or intranasal, including 4 viral vector vaccines and a protein subunit vaccine. They have each been authorized in one or 2 countries: China, India, Indonesia, Iran, Morocco, and Russia.
The next mucosal vaccine on the rollout horizon could potentially be from the US company, Codagenix. A single dose spray of this vaccine has been in phase 2/3 as part of the large placebo-controlled WHO Solidarity Trial for Vaccines since August 2022. And there will be a large phase 2b trial as part of Project NextGen in the US this year. A spokesperson for the company has said they hope to be ready to submit to the FDA this year.
Another Covid vaccine that has a mucosal version may be getting close to authorization, though it’s not clear if that would include the intranasal booster. Called Patria, it’s a version of the Mount Sinai/Castlevax vaccine, developed in Mexico by Avi-Mex.
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Mucosal vaccine news
I didn’t find any new clinical results for mucosal Covid vaccines in the last month or so. However, a phase 1 trial of an intranasal protein subunit vaccine developed by Intravacc (Netherlands) is now fully recruited, with results expected soon.
In addition, CyanVac updated the phase 2 trial record of their intranasal viral vector vaccine in late December. They now expect the trial to be fully recruited in April, with 400 participants receiving doses.
I’ve added 10 preclinical reports on results for mucosal vaccines to my collection. These include:
A study at Beth Israel Deaconess Hospital in New York found “near complete protection” from Omicron challenge (BQ.1.1) in rhesus macaques after intratracheal administration (into the windpipe) – both intranasal and intramuscular administration weren’t as effective.
A viral vector vaccine (MVA) developed by the Centro Nacional de Biotecnología (CNB CSIC) in Madrid was adapted to the Beta variant. In a study comparing this with the original version in mice, a single intranasal dose protected against lethal Beta variant challenge as well as 2 intramuscular doses. There were also signs of immunity to a range of Covid variants.
A study in hamsters by a team from Duke-NUS Medical School and the National University of Singapore compared intranasal doses to injections, and reported that immune system effects after the intranasal version lasted longer, and showed responses to more variants
See also the section on pancoronavirus vaccines, which includes news on another 2 intranasal vaccines.
Mucosal Covid vaccine overview:
Mucosal vaccines are currently authorized for use in 6 countries.
27 have reached clinical trial, with at least one of those has been discontinued. These are tracked in a table below.
6 mucosal vaccines have reached phase 3 trials, including the 5 authorized vaccines.
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Durable or “variant-proof” vaccine news
This is a rather vague category, including vaccines that aim to be more durable. I don’t include a table for tracking these vaccines. That’s because while I’m quite confident I’ve tagged all the vaccines in my collection that fall into the other 2 categories of next generation vaccines, I’m not sure how many can be classified as aiming to be “variant-proof”.
The big news this update is LUNAR-COV19, the recently authorized SAM from Arcturus. I’ve included an overview of all the clinical trials for this vaccine, including one published in December. After that, there are 2 new preclinical studies for other vaccines.
LUNAR-COV19 (Arcturus, USA):
This SAM vaccine has been adapted for recent variants, but the version that has been authorized is an earlier one, called ARCT-154. You can dig into all the records in my collection for all versions here.
Overview of the trials for the LUNAR-COV19 series:
Phase 1 and 2 trials of an earlier version, ARCT-021, in Singapore, with 42 and 64 participants respectively (published December 2022).
A phase 2 trial of ARCT-021, in Singapore and the US, with 581 participants. Unpublished (trial registry record).
A phase 1 to 2 trial of 3 versions as a booster, ARCT-021, ARCT-154, and ARCT-165, in Singapore and the US, with 72 planned participants. There is a poster of results for 36 participants, 12 for each vaccine, suggesting immune response is durable to at least a year (September 2023).
A phase 1 to 3 trial of ARCT-154, in Vietnam, with around 1,000 in earlier phases and over 16,000 in the placebo-controlled efficacy part of the trial. Preprint (September 2023).
A phase 3 immunogenicity and safety trial of ARCT-154 as a booster, in Japan, with 828 participants randomized to a LUNAR-COV19 or BNT/Pfizer booster (published December 2023, previously a preprint, July 2023).
The trial in Vietnam is this vaccine’s efficacy trial. It was placebo-controlled, running during Delta and Omicron waves in Vietnam. Of the over 16,000 participants, 17% were aged 60 or over, and 35% of the participants under 60 had co-morbidities.
There were 2 injections, 28 days apart. Efficacy:
Any confirmed Covid: 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 rate of systemic adverse events was close to 50% for the first dose in phase 3, and close to 75% in the earlier phases – and lower for the second dose. That was roughly similar to the BNT/Pfizer and Moderna trials, but the rate of severe events was less than 1%. For context, the most common severe event for BNT/Pfizer was 4% for fatigue; for Moderna, it was 10% for fatigue.
In the head-to-head randomized booster trial, the participants had all had 3 doses of either BNT/Pfizer or Moderna mRNA vaccines: 420 got a LUNAR-COV19 booster (5 μg) and 408 a BNT/Pfizer one (30 μg). Almost all were under 65 years of age (98%) and had had their 3rd mRNA shot 5 or more months previously (98%). Most had been fully vaccinated with BNT/Pfizer (80%), and all but 1 of the rest had 2 doses of Moderna followed by a BNT/Pfizer booster.
The rate of systemic adverse events was similar (66% for LUNAR-COV19 vs 63%). The rate of severe adverse events was 2% for LUNAR-COV19 and 4% for BNT/Pfizer.
The measures of immune response for LUNAR-COV19 at 28 days were non-inferior for the original Covid strain compared to BNT/Pfizer, but for Omicron BA.4/5.
We don’t have durability data yet for any of the large trials. Durability for the head-to-head trial will be reported later for 3, 6, and 2 months after vaccination.
Preclinical studies for other vaccines:
TU88mCSA and ALCmCSA, mRNA vaccines from Tufts University (USA): In this paper, the group reports a high level of protection against Omicron variants in hamsters, including lower viral load in the upper airways.
GLB-Cov2-043, an mRNA vaccine from GreenLight Biosciences (USA): A study in mice and hamsters, including Omicron challenge. (All records on the GLB-Cov2 vaccines.)
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Pancoronavirus vaccine news
Background re-cap:
We’ve had major human epidemics or pandemics of 3 dangerous coronaviruses – 2 types of SARS, plus MERS. There are many other coronaviruses circulating among animals, too. Pancoronavirus vaccines aim to provide protection not only from variants of the SARS virus that causes Covid, but also some against the next new coronavirus that’s likely to spread among us.
Pancoronavirus vaccines aren’t as far along the development path as the other categories above. A table below this post keeps track of those with publicly available preclinical results. As far as I know, there are still only 3 vaccines in this category in phase 1 trials, with a fourth planned to start in early 2024:
DIOSynVax (Cambridge University spin-off, UK);
INSERM (France) – not yet underway;
VBI Vaccines (Canada); and
Walter Reed Army Institute of Research (WRAIR, USA).
New this update:
Duke University’s protein subunit vaccine: In a new preclinical study, the team reports the results of testing a modification of the vaccine in primates and non-primates. I have also added a 2021 paper I had missed, in which the vaccine is studied in primates.
University of Washington’s protein subunit vaccine (with SK Bioscience): There’s a new report of testing design modifications in mice for this vaccine. A study previously available in preprint has now been published. In 2022, this group had hoped to be in a first-in-human clinical trial by the end of 2023 – I haven’t seen a report of their current timetable.
NILV-PanCoVac, an intranasal viral vector vaccine from Charité Universitätsmedizin Berlin: This vaccine is new to my list, but the study isn’t new – I had missed a publication from July 2023. This reports on an early study in hamsters, with a SARS-CoV-2 challenge test after a single low dose.
Finally, a preclinical study that was previously available as a preprint is now published, for the intranasal viral vector vaccine from the University of California Irvine and Techimmune.
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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 – I’ve marked that with an asterisk*. 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).
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Addendum 2: 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.
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Addendum 3: Pancoronavirus vaccines with preclinical results
* Indicates new entry since previous update post.
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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).
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You can keep up with my work at my newsletter, Living With Evidence. And I’m active on Mastodon: @
[email protected]
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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:
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.)
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