(C) PLOS One [1]. This unaltered content originally appeared in journals.plosone.org. Licensed under Creative Commons Attribution (CC BY) license. url:https://journals.plos.org/plosone/s/licenses-and-copyright ------------ Adapting for Variants: Early Results or Trials Underway for 38 Versions of 17 Covid Vaccines [] Date: 2022-02-23 00:00:00 Seventeen vaccines with at least one variant-adapted version sounds like a lot. But none are actually in use yet. And given all the hype about how quickly and easily adapted vaccines could be delivered, it’s remarkable how little data we’ve seen well over a year since the first variant of concern emerged. We had gotten used to a high level of transparency about the development of the Covid vaccines leading the pack in the US and Europe. That’s not the rule any more. For example, I haven’t been able to find any preclinical reports for the various BNT/Pfizer adapted versions in clinical trials, including for the Alpha variant. Another example: even when there are late stage clinical trials, protocols aren’t to be found, either. Before we get to the studies and results we can see, let’s zoom out to the big picture. Several vaccination strategies are being studied for expanding or strengthening our immune systems against Covid variants: Boosting with an additional dose of the same vaccine; Boosting with a dose of a different vaccine (heterologous vaccination); Adapting a vaccine for a variant; Multivalent vaccines – combinations of original plus adapted version(s), or combinations of adapted versions; Vaccine so wide-ranging, it’s hoped to be more or less variant-proof – or even effective for all coronaviruses. I posted a roundup of evidence and ongoing trials for the first 2 of those strategies in late January. In general, they both increase protection against variants, with heterologous boosting often making a particularly large difference for vaccines with somewhat lower initial effectiveness. (That post included a table listing laboratory studies of responses to Delta and/or Omicron after boosters: an updated version of that is below this post.) This post is looking at the next 2 strategies: adapted and multivalent vaccines. My key takeaways? We seem to be on the brink of seeing meaningful clinical trial results for some adapted vaccines. And from the research results that have been released so far, it seems likely that at least some of these vaccines will provide better protection against the variants circulating now – and, critically, perhaps broaden immunity enough for greater protection from the next ones. Just as the original vaccines based on the virus’ early strains reduced the risk of severe outcomes from variants that were very different, adapted vaccines based on variants that are no longer a threat could do that, too. For example, as we’ll see later in this post, a “press teaser” finding from a randomized trial suggests the Alpha-adapted BNT/Pfizer vaccine could possibly be substantially more protective against Omicron than the original formulation. (Proviso here: the companies released far too little information about this to be sure about how good it was.) And Sanofi’s Beta-adapted protein subunit vaccine may even have increased the potential for protection against original SARS in a preclinical study. On the other hand, some don’t work as well as another shot of the original. This next stage of vaccine development is very complex, as researchers grapple with a shape-shifting virus, and the complexity of so many possible vaccine adaptations, too. Multivalent vaccine development escalates that complexity: that’s a mixture of vaccines in one dose, which adds questions to the list about multiple possible vaccine combinations and how much of each to add to the mix. All this comes as an overlay to the complicated issues of boosting with different vaccines if/when we have adapted vaccines tested only in people who had that same vaccine. Today, 63% of the world’s people have had at least a dose of a vaccine – and it’s a real patchwork of vaccines, often changed up along the way to 2 or 3 shots. And as if all that isn’t complex enough, there’s the question of intranasal administration: one of the vaccines in this post suggests that could make a meaningful difference for at least some adapted vaccine boosters. There’s lots more to cover, though, so let’s dig in. Here’s how I’ve broken this post down: Overview of vaccines, variants, and studies I found 37 studies reported or underway for 38 adapted vaccines or combinations, from 17 vaccine groups – 7 of which have original formulations of vaccines in use in at least one country. Most are mRNA or protein subunit vaccines. There are sure to be other adapted versions that don’t have published results or clinical trials registered, or for vaccines that are earlier in the pipeline, so expect a stream to keep coming. (I monitor vaccines when they release preclinical or clinical results, as well as any that have announced a phase 3 trial.) The vaccines in this collection include adaptations for 4 of the 5 variants of concern – none are for Gamma. There are vaccines adapted to 1 or 2 of them, and one vaccine adapted to all 4. The variants of concern so far have points in common as well as differences with the original virus that vaccines were formulated to recognize. Here’s a diagram showing how much the 5 variants of concern vary genetically (by Stuart Ray of John Hopkins): Representation of Covid variants of concern based on NextStrain data via Wikimedia Commons Another variant of concern could be close to what we’ve already encountered – or it could strike out in a newer direction, as Omicron did. The studies on the impact of adapted vaccines will help us learn what can strengthen immune systems to face SARS-CoV-2 variants. The studies tallied in this post include: Results of 19 preclinical studies. 18 clinical trials underway, mostly phase 2, for close to 16,500 participants globally. Results for subsets of clinical trial participants for adaptations of 1 vaccine (Moderna), and some fragments of data from another (BNT/Pfizer). Most of the vaccines are ones that aren’t yet rolled out in their original formulation – and for one of them, the first formulation is already adapted for variants (Alpha and Beta, with a later version covering Alpha, Beta, Delta, and Omicron). The 17 vaccines that have adapted versions include: 7 mRNA vaccines and 1 self-amplifying RNA, 5 protein subunit vaccines, 2 adenoviral vector vaccines, 1 inactivated vaccine, and 1 DNA vaccine. (One of the mRNA vaccines is lyophilized (freeze-dried) and one of the protein subunit vaccines has an intranasal version of adapted vaccine.) 7 that are already in use in original formulation (AstraZeneca, BNT/Pfizer, CovIran (Shifa Pharmed), J&J, Medigen, Moderna, Novavax) – 4 of those with adapted versions in clinical trials (AZ, BNT/Pfizer, Medigen, and Moderna). 12 that are multivalent, and another that’s called a hybrid – it’s not a mix of 2 vaxes, but it’s targeted to 2 variants. They’re nearly all bivalent – including 2 versions of the vaccine – but one is quadrivalent: for protection against 4 strains of the virus (Alpha, Beta, Delta, and Omicron). Digging into the results Overall, there is a lot of uncertainty around these findings. They are almost all very small, preclinical studies. Some carry more weight than others, though, because they’re better-designed and conducted, with better reporting of what was done. Animal results aren’t going to be a precise substitute for what happens in people, but there’s a spectrum here, too. Data in non-human primates is likely to be closer to what could be expected in humans, for example. Confirmation of results in experiments in more than one type or species of animal strengthens confidence in the reliability of conclusions, as well. And there can be differences between the techniques used in the studies – such as whether researchers analyzed immune responses in enough ways, and used tests based on actual viruses, or pseudovirus tests only. There are 2 broad types of preclinical studies here: Studies of potential immunity only – analyzing immune responses in the animals, to identify whether they might be able to provide protection against particular variants; Challenge experiments, where the researchers try to infect the animals with virus after vaccination, and then analyze immune responses as well as other outcomes like weight loss (which suggests severe disease), and infection and viral loads. Although I looked at a range of aspects of the studies to consider how to weigh them, in my opinion, whether or not the researchers included challenge experiments and/or randomized non-human primates turned out to be markers for dividing this set of studies into a “stronger” and a “weaker” group. I’ve also looked at what the researchers conclude about antibody/antigenic imprinting (“original antigenic sin”). That’s when the immune system is so firmly influenced by a first encounter to a vaccine or antigen, its responses are heavily shaped by that original memory. (Derek Lowe discusses this phenomenon here). If that happens with a Covid vaccine, then a variant-adapted booster mightn’t have much impact. But I don’t have the technical expertise to discuss the design choices of the various adaptations made to the vaccines, and their possible implications. First up, I’ve got a table showing the variant-specific vaccines that have public results, tagging those that have challenge experiments. After that, I discuss some issues I think are noteworthy, followed by a brief overview of results, vaccine by vaccine. That’s broken down into a pair of tables – for those with stronger and weaker evidence – so that the ones I think have greater uncertainty are clearly separated. There are links to get you to the studies in 2 places: the overviews include links to the records for the vaccines in my collection – split into the ones for adapted vaccines, and all records. That’s a lot to navigate for the vaccines with many studies, though. So there are links to each individual study, whether or not they have results, in the full list of studies. Vaccines with results for adapted versions for variants * Includes challenge experiment(s) Variant Preclinical (non-human animals) Clinical (human) Alpha HDT Bio (saRNA)* BNT/Pfizer Beta ACM Biolabs (protein subunit – intranasal)* AstraZeneca (AZ) (adenoviral) Clover (protein subunit) HDT Bio (saRNA)* J&J (adenoviral) Moderna (mRNA)* Novavax (protein subunit)* Sanofi (protein subunit) Moderna Delta Academia Sinica Taiwan (mRNA) Shenzhen Rhegen (mRNA – lyophilized)* BNT/Pfizer Moderna Omicron Academia Sinica Taiwan (mRNA) Chinese Academy of Military Sciences/Walvax (mRNA) Chinese Academy of Sciences (mRNA) CovIran (Shifa Pharmed) (inactivated) HDT Bio (saRNA) Moderna (mRNA)* Shanghai Key Laboratory Fudan (DNA) Shenzhen Rhegen (mRNA – lyophilized)* There’s a lot of variety in these experiments – for example, whether or not they were testing the vaccine as a booster or a primary series (the first vaccination cycle, which is usually 2 shots). And there’s a lot of variety in the results, too. Most of the researchers conclude the vaccines could be an improvement on original formulations, but we won’t know if the differences are meaningful until we see how they work in people. The question of “antigenic sin” has gotten a fair bit of attention in discussions on social media, as some researchers have suggested it might be a factor in the results of the vaccine they studied. However, most don’t. Some of the “weaker” group of studies either didn’t test the vaccine as a booster, or had no comparison group, so the question is very open for them. There are only reports from studies in humans for 2 vaccines, BNT/Pfizer and Moderna. For the first, BNT/Pfizer’s, it’s results from a randomized trial – but it was just a single slide in a press briefing, with nowhere near enough information to know how certain we can be about the results presented. It was for the ability to neutralize Omicron after vaccination with an Alpha-adapted variant, one for Delta, or a bivalent one of both. That they had this data suggests that BNT/Pfizer will be first past the post in the late stage clinical trial results race again. The second, Moderna’s, has plenty of data, but it’s actually more complicated. While I think researchers for this vaccine had the strongest methodology of any of the preclinical studies (by Ying and colleagues, 2021), the clinical research reports are problematic. They are 2 exploratory studies, where they’ve taken small subsets of participants from more than a single study each time, without the selection process being fully described, and with other factors driving up the risk of bias. For now, then, we’re really left with the preclinical studies. So finally, some points I think are noteworthy from those: When an adapted vaccine didn’t seem to do better than the original vaccine, that tended to be because of apparently weaker potential to protect against other versions of the virus it wasn’t targeted at – the adapted vaccines typically worked well against the variant they were aiming for. Multivalent vaccines didn’t always do better, but they mostly worked at least as well as the most protective vaccine in the mix, and sometimes better. The number of variants tested for ability to respond in these studies was often quite small: many were done before the recent variants had emerged, for example. Still, many of the vaccines seemed to have a very broad range of potential protection. I already mentioned an example of one that was widely tested: Sanofi’s protein subunit vaccine may even have increased protection for the original SARS, which is a different coronavirus. (It improved outcomes for all the SARS-CoV-2 variants tested, too – original, Alpha, Beta, Gamma, and Delta.) One of the mRNA vaccines was lyophilized (freeze-dried) – from Shenzhen Rhegen Biotech and other collaborators in China. As I mentioned early in this post, there was an intranasal version of an adapted vaccine in this set of studies, and that may have enhanced its potential effectiveness. It’s for the protein subunit vaccine from ACM Biolabs (a company based in Singapore and Switzerland). (There are quite a lot of studies on intranasal or other mucosal delivery of a variety of Covid vaccines, but I haven’t added a tag for that yet in my collection – though I’m sure that’s just around the corner!) Overview of results for stronger studies* * Includes challenge experiment and/or randomized non-human primates, and additional stronger preclinical research methods, such as live virus assays, multiple animal types, and/or randomization of other animals. ** Includes include clinical research. Vaccine Variant(s) Signs of improvement over original? Records **BNT/Pfizer (mRNA) Alpha, Alpha+Delta Possibly yes (as a booster) (Only tested against Omicron) Adapted All HDT Bio (saRNA) Alpha, Beta, Omicron Possibly yes (alone as a primary series) Possibly not as a booster* (*Only Omicron version tested as booster) Adapted All ACM Biolabs (protein subunit) Beta, Original+Beta Possibly yes for intranasal version (alone as a primary series) Multivalent, possibly not* (*Not tested in an intranasal version) Adapted All J&J (adenoviral) Beta Possibly yes (as a booster) Adapted All **Moderna (mRNA) Beta, Original+Beta, Delta, Beta+Delta, Omicron Mixed results – roughly similar to original Adapted All Novavax (protein subunit) Beta, Original+Beta Possibly yes (alone or as booster) Adapted All Sanofi (protein subunit) Beta Possibly yes, adjuvanted or multivalent (as booster to the original vax or Sanofi’s mRNA vax) Adapted All Shenzhen Rhegen (mRNA, lyophilized) Delta, Omicron Possibly yes for Delta adaptation (alone as a primary series) (Possibly not for Omicron adaptation – weaker evidence) Adapted All Overview of results of weaker studies Vaccine Variant(s) Signs of improvement over original? Records AstraZeneca (adenoviral) Beta, Original+Beta Possibly not (as primary series or booster) Adapted All Clover (protein subunit) Beta, Original+Beta Possibly yes (as primary series or booster) Adapted All Academia Sinica Taiwan (mRNA) Delta, Delta+Omicron, Hybrid with characteristics of Delta and Omicron Possibly yes (as primary series for Delta and Delta+Omicron versions) Possibly not for Omicron or hybrid versions Adapted All Chinese Academy of Military Sciences/Walvax (mRNA) Omicron No data for comparison to original Adapted All Chinese Academy of Sciences (mRNA) Omicron Possibly not (as primary series – not tested as booster) Adapted All Shanghai Key Laboratory Fudan (DNA) Omicron Possibly yes (as a booster) Adapted All Shifa Pharmed (inactivated) Omicron No data for comparison to original Adapted All Full list of studies on variant-adapted Covid vaccines and combinations Listed alphabetically by vaccine technical name; booster status detailed when previous vaccine is from a different developer * Original vaccine rolled out in at least 1 country in February 2022 Back to list of contents ~~~~ 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. Notes on my collection of studies are here. The collection is in a public Zotero library you can dig into here. 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.) The representation of similarity between Covid variants of concern comes from Wikimedia Commons, based on data from NextStrain on December 1, 2021 by Stuart Ray from Johns Hopkins (wiki name, Soupvector). Updated list of laboratory studies including responses to Delta and/or Omicron after boosters This is an update of a list included in a post from late January, including a summary of the studies up to January 25. Vaccine(s) Type of study Variants of Concern Results 3rd dose of Sinovac’s CoronaVac Humans, blood tests Beta, Gamma, Delta Wang (Sept 5) 3rd dose of Moderna’s vax, either adapted for Beta or original or multivalent (combination of original and adapted in one dose) Humans, blood tests Beta, Gamma, Delta Choi (Sept 15) 3rd dose of Sanofi’s protein subunit vax (original & version adapted for Beta), after doses of that vax or their mRNA vax Preclinical, non-human primates Alpha, Beta, Gamma, Delta Pavot (Sept 21) 2nd or 3rd dose of Medigen’s protein subunit vax adapted for Beta, after dose(s) of original, and 3 doses of original Preclinical, non-primates Alpha, Beta, Gamma, Delta Kuo (Oct 15) 3rd dose of Sinovac’s CoronaVac Humans, blood tests Alpha, Beta, Delta Yue (Oct 19) 3rd dose of Moderna, either adapted for Beta or original Preclinical, non-human primates Beta, Delta, Epsilon, Gamma, Iota Corbett (Oct 21) 3rd dose of Sinopharm’s Beijing vax Humans, blood tests Beta, Delta, Lambda Ju (Nov 10) 3rd dose of Pfizer Humans, blood tests Delta, Omicron Basile (Dec 13) 2 or 3 doses of Pfizer, 1 dose of J&J, or 1 or 2 doses of Moderna Humans, blood tests Omicron Schmidt (Dec 13) 2-dose course of Moderna followed by half-dosage Moderna Humans, blood tests Beta, Omicron Doria-Rose (Dec 20) 3rd dose of Moderna in half and full dosages, original, adapted for Beta or Omicron, or multivalent Humans, blood tests Omicron Moderna press release (Dec 20) 2-dose course of Sputnik V (Sputnik Light [rAd26-S] followed by second Sputnik V vaccine [rAd5-S]), followed by another dose of Sputnik Light Humans, blood tests Omicron Dolzhikova (Dec 21) 3rd dose of Moderna or Pfizer in people with multiple sclerosis on anti-CD20 treatment Humans, blood tests Delta, Omicron Madelon (Dec 21) 2 doses of Novavax followed by a 3rd dose Humans, blood tests Delta, Omicron Novavax press release (Dec 22) 2-dose courses of Moderna or Pfizer or single-shot J&J; additional mRNA vax (as 3rd after mRNA or 2nd after J&J), either homologous or heterologous Humans, blood tests Delta, Omicron Garcia-Beltran (December 23) 3 doses of Pfizer Humans, blood tests Delta, Omicron Hoffmann (Dec 23) 3rd dose of Pfizer Humans, blood tests Delta, Omicron Ariën (Dec 24) 2 or 3 doses of Pfizer Humans, blood tests Delta, Omicron Lusvarghi (Dec 28) 2-dose course of AZ, Moderna or Pfizer or single-shot J&J; dose of Pfizer after 2-dose Moderna or single-shot J&J Humans, blood tests Beta, Delta, Omicron GeurtsvanKessel (Dec 29) (Feb 4) 2-dose course of CoronaVac followed by a dose of Pfizer Humans, blood tests Delta, Omicron Perez-Then (Dec 29) 2-dose course of AZ, Moderna or Pfizer; 3rd dose of Pfizer after AZ, Pfizer or Moderna 2-course; 3rd dose of Moderna after AZ 2-course; Moderna or Pfizer dose after single-shot J&J Humans, blood tests Omicron De Marco (Dec 30) 2-dose course of Pfizer followed by 3rd dose of J&J or Pfizer Humans, blood tests Omicron Tan (Dec 30) 2-dose courses of Pfizer or Moderna or 3rd dose of Moderna or Pfizer Humans, blood tests Beta, Omicron Carreño (Dec 31) 2-dose course of Moderna or Pfizer or single-shot J&J; booster dose of Moderna or Pfizer Humans, blood tests Delta, Omicron Saharia (Jan 1) 3-dose course of AZ or Pfizer Humans, blood tests Alpha, Beta, Gamma, Delta, Omicron Dejnirattisai (Jan 3) 2-dose course of AZ, Moderna, or Pfizer; 2-dose course of AZ or Pfizer with 3rd dose of Moderna or Pfizer Humans, blood tests Alpha, Delta, Omicron Willett (Jan 3) 2-dose courses of AZ, Moderna and/or Pfizer with 12-week interval; 2-dose course of Pfizer with short interval with 3rd dose of Moderna or Pfizer Humans, blood tests Delta, Omicron Belik (Jan 5) 2-dose courses of CoronaVac or Sinopharm Beijing with 3rd dose of either Moderna or Pfizer Humans, blood tests Beta, Delta, Omicron Zuo (Jan 6) 2-dose courses of AZ or Pfizer with third dose of Pfizer Humans, blood tests Delta, Omicron Faustini (Jan 8) 1 to 3 doses of Moderna or Pfizer Humans, blood tests Beta, Delta, Omicron Banerjee (Jan 13) 2 doses of J&J; 2 doses of Moderna with 3rd half- or full-dose Moderna; 3 doses of Pfizer; 2 doses of Pfizer with 3rd dose of J&J; 1 dose of J&J with Pfizer 2nd dose Humans, blood tests Omicron Lyke (Jan 14) 2-dose course of Sinopharm Beijing; 3-dose course of Sinopharm Beijing or 3rd dose of ZF2001 Humans, blood tests Omicron Wang (Jan 15) 2-dose course of Moderna or Pfizer with 3rd dose of Moderna or Pfizer Humans, blood tests Omicron Jergovic (Jan 16) 3-dose course of Pfizer Humans, blood tests Beta, Delta, Omicron Muik (Jan 18) (by BioNTech/Pfizer) 2-dose course of CoronaVac or AZ, or 3-dose course of AZ Human, blood tests Alpha, Beta, Delta, Omicron Suntronwong (Jan 18) 3-dose courses of Moderna or Pfizer Human, blood tests Beta, Delta, Omicron Walls (Jan 19) 3-dose course of Pfizer Human, blood tests Omicron Wu (Jan 19) 2- and 3-dose courses of Pfizer Human, blood tests Omicron Xia (Jan 22) 2-dose courses of AZ or Pfizer, 3rd dose Pfizer (people with cancer) Human, blood tests Omicron Fendler (Jan 25) 2-dose course of Pfizer, 3rd dose Pfizer (longitudinal study) Human, blood tests Alpha, Beta, Gamma, Delta, Omicron Wratil (Jan 28) 2-dose course of Moderna or Pfizer, 3rd dose of same (longitudinal study of healthcare workers) Human, blood tests Beta, Delta, Omicron Debes (Jan 31) 2-dose course of Moderna, 3rd dose of Moderna or Moderna adapted for Omicron Preclinical, non-human primates Omicron Gagne (Feb 4) 2-dose course of Pfizer or 1-dose J&J, 3rd dose of Pfizer or J&J Preclinical, non-human primates Delta, Omicron Chandrashekar (Feb 7) 2-dose course of Moderna or Pfizer, 3rd dose of Moderna or Pfizer Human, blood tests Omicron (BA1, BA2) Iketani (Feb 9) 2-dose course of Moderna, 3rd dose of Moderna or Moderna adapted for Omicron Preclinical, mice Omicron Ying (Feb 9) 2-dose course of Moderna or Pfizer, 3rd dose of same vaccine (people who had breakthrough infections) Human, blood tests Delta, Omicron Gaebler (Feb 11) Back to list of contents [END] [1] Url: https://absolutelymaybe.plos.org/2022/02/23/adapting-for-variants-early-results-or-trials-underway-for-38-versions-of-17-covid-vaccines/ (C) Plos One. 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