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SinoPharm’s Inactivated Coronavirus Vaccine

So now we have some clinical data on yet another category of vaccine: SinoPharm’s inactivated coronavirus candidate. This is one of the classic vaccine techniques, where an infectious virus is altered by some sort of protein-denaturing treatment (heating or reactive chemistry) to make it noninfectious. But such particles can retain enough of their protein surfaces to set off a useful immune response – the tricky part is inactivating the virus enough so that it can’t infect cells and replicate, but not so much that it presents totally different proteins to the immune system and raises a response that won’t help against the real virus.

In SinoPharm’s case, they inactivated the coronavirus with beta-propiolactone, which is a classic protein-alkylating compound. BPL is a strained four-membered ring that is ready to be attacked and opened by pretty much any sort of nucleophile, including protein side chains from amino acids such as Cys or Lys. The compound is used for chemical disinfection (surgical instruments and the like), but that’s not a casual application, because it’s carcinogenic by itself. It works out for such applications, though, because it’s very volatile (and thus easy to remove by vacuum or heating), much like another small reactive and toxi) strained ring compound, ethylene oxide. So there’s no danger in using BPL to inactivate a virus – the question, as mentioned, is going to be whether you’ve inactivated it too much.

Patients in the Phase I trial got 2.5, 5, or 10 micrograms of this agent at Day 0, Day 28, and a third time at Day 56. There were 24 patients in each group, plus an equal-sized placebo group that just got alum adjuvant injections. In the Phase II trial, the 5 microgram dose was chosen, and there were two groups: injection at Day 0 and Day 14, or injection at Day 0 and Day 21, with 84 patients in each group and a 28-patient placebo group for each. Median ages were around the early 40s, slightly more men than women. Adverse reactions appear to have been nothing remarkable – pain at the injection site mostly, with very little systemic stuff like fever or fatigue, which certainly appears to be the mildest profile of the vaccines that we’ve seen so far.

As for neutralizing antibodies, it looks like the three-dose Phase I trial had an odd dose-response. The medium dose was actually slightly worse than either the low or high one. Meanwhile, in the Phase II, which was done with that medium five-microgram dose, the antibody response (measured two weeks after the second dose) was not as strong as with the full three-dose schedule, but the 0/21 day dosing schedule led to a better response than the 0/14 one. It appears from the Phase II data that one of the 42 patients who were tested for antibody response in that group did not seroconvert at all. The geometric mean titer values for the neutralizing antibodies (247 for the 0/21 group) appear to be in the range of other Phase I data reported, although it’s not easy to make a head-to-head comparison with any certainty. There is no comparison in the study with a convalescent plasma group, but as we’ve been seeing, those samples tend to be pretty variable themselves. There are also no data on T-cell responses.

So this is a rather preliminary report (as the authors themselves note), but it’s the first one we have on an inactivated vaccine. Like all of the others so far except the J&J Ad26 one, this candidate will also need a booster shot. The small and mild adverse-event reactions here are really the main thing that stands out – if you’re a glass half full person, then you can be glad about that, but if you’re a glass-half-empty one, you might wonder about the overall robustness of the immune response (update: see here for more on this issue). We’re going to need more data to make any calls about that, and (just as with every other vaccine under development!) the real numbers we’re waiting on for efficacy. How many people will this (or any) vaccine protect, and how well? Stay tuned.

 

42 comments on “SinoPharm’s Inactivated Coronavirus Vaccine”

  1. SirWired says:

    You *know* that if this vaccine goes anywhere, the anti-vaxxers are going to be all over it with “Beta Propiolactone is used to make it, and it’s a carcinogen! Just look here! [Link to MSDS]. #VaccinesArePoison #BillGatesConspiracy #SomethingSomethingChina” The fact that there will be little, if any, detectable amount in a tiny vaccine dose will be conveniently ignored.

    1. Duncan says:

      But it does raise a more serious wider issue I think. I realise that this might not go down very well with a lot of people, but…..

      What I do think that this pandemic has shown is that science and scientists seriously need to have a thorough rethink about their relationship with the media and, in particular, social media. It’s all well and good taking the view that science is somehow special and sacrosanct. To be clear I believe that it does have a special quality that sets it apart from other disciplines. But once you start to take science to social media, that’s it. The point of social media is not that everyone open-mindedly steps upto social media to dumb up. The culture of social media is that anything and everything is there to be shot at and no one can control the narrative that emerges easily. What you think about that is another matter – it is what it is. If anti-vaccine controls the narrative then that’s what happens.

      I do feel that on occasion scientists have been at best naive and at worst have seen what they want to in social media. Indeed one could very reasonably I think make the case that science on a twitter thread alongside personal politics is, however inadvertent, politicising the science. If a vaccine is ever found it will be the most almighty internet bunfight and it will spill over into flesh-and-blood reality and I get no feeling that science, or politics, is ready for it. As the saying goes, if you are explaining you are losing.

      To be very clear I make no criticism of Derek Lowe here – these articles have been excellent and exactly what the mainstream media should be like. And, of course, perhaps not much of what I see is new per se. Had social media been around the Spanish flu we’d probably have seen much the same as we see now.

      But science I feel needs to seriously wise up about its relationship with social media sooner rather than later.

      1. Omar Stradella says:

        I don’t know what you expect scientists to do. Anti-vaxing is like a religion, it spreads like a religion, and there’s nothing that you can say to their followers that will change their mind. There’s always been nonsense through history, but it’s only in recent times that nonsense has been able to spread beyond its natural limits thanks to “social media.” Before social media, nobody would think that giving a forum to the fringe elements of society was a good idea. The problem is that social media companies only care about making money and they are very reluctant to take any actions that could affect their bottom line.

        1. Duncan says:

          Omar Stradella – Thank you for your reply. Inevitably the problem is easier to state than is the solution! You say, ‘Before social media, nobody would think that giving a forum to the fringe elements of society was a good idea.’ Well….we aren’t before social media now and what I think that science has been slow to grasp is that things that were once fringe ideas with a limited audience are now not fringe any more. The ‘problem’ is very much not that social media companies exist to make money any more than any other corporate exists to make money. The problem (if you see it as one) is that science, like everything else is there to be torn down on social media. You may well see this a bad thing or a side-effect – indeed I can remember in 2009 I was laughed out of a room when I said that all this would happen. But it’s happened and the world is different now and I don’t think that science communication has caught up. For good or for ill science is and scientists are there to be shot at. Anti vaccine is just the most grisly example.

          You ask what I think should be done and I have no easy answers. I think that scientists perhaps have not always thought through the implications of making personal political statements alongside presenting their science on (for example) twitter. That’s not so say that scientists should be silent on the issues of the day, rather it is to say that putting partisan political views next to science is not implication-free. I think that science does sometimes have an unfortunate habit of coming across as being hectoring. Perhaps that’s the nature of social media. But above all I think that science needs to get out of the habit of seeing things on social media as fringe. That’s not what social media is about, rather it is (notionally) about the freest of speech, even if it’s not agenda-free speech.

          It’s not science’s fault, and science is far from alone in needing to take a less rose-tinted view of the internet. But the vastly altered media landscape we now have is, fair or not, science’s problem. I don’t always get the impression science understands this state of affairs.

          1. Eefex says:

            It’s pretty hard not to make political statements as a scientist when we’ve managed to politicize anti-scientific beliefs. And, frankly, it’s inevitable that something like that is going to happen when you have such large groups of anti-science people gathering online. Ultimately a politician’s success depends on their ability to identify and appeal to groups like that and the most cynical ones will have no issue reaching out.

          2. David G Whiteis says:

            . . . and, of course, depending on one’s definition of “political,” it’s almost imossible NOT to “politicize” science. If environmental research finds data showing that global warming is a threat, and if the only possible approach to solving this problem is through drastic social and economic restructuring, that’s a “political” conclusion as much as it is an “objective” one.

            More pertinent to this discussion: If the data show that low-income and “minority” people and communities are at disproportionately higher risk for COVID infection and/or death (i.e., social inequality is pathogenic), then once again we have a “politcal” situation demanding resolution.

            That being said, I agree 100% that the ongoing tweeter-twitter-twatter drivem dumbing-down of virtually all life to the lowest common denominator is a pandemic in and of itself, for which there is no vaccine.

          3. confused says:

            >>. . . and, of course, depending on one’s definition of “political,” it’s almost imossible NOT to “politicize” science.

            True to a degree, but I think it is still important to distinguish the science itself from the political/policy or ethical side.

            IE, science can say, “given these assumptions/models and data, if nothing changes, ABC will happen, within a given margin of error. These possible changes XYZ will have these effects, within a given margin of error” (whether that’s pandemic spread or climate change or whatever).

            Saying “therefore we should do X and not Y or Z” is not really a scientific statement itself, it is dependent on ethical values, and ethical values are not accessible to science per se. Also, there may be political and structural limitations such that actually doing X is not feasible and so an apparently inferior solution is actually the better bet (since it has a much better chance of actually being done).

            I think the distinction is important because expertise in the science side doesn’t necessarily confer any “intellectual authority” on the ethical, policy, or economic side.

        2. Anonymous says:

          Niall Ferguson “The Square and the Tower”

        3. Vader says:

          “Anti-vaxing is like a religion”

          That strikes me as an insult to most of the religions I’m familiar with.

      2. x says:

        You’re blaming social media for something I think it only reflects: a societal lack of faith in institutions, including scientific institutions, and a corresponding tendency to embrace countercultures. And this is not new; anti-intellectualism has been spreading for decades.

        I’m a bit of a Marxist, so my explanations for social phenomena often run to class, and I think it works here; there’s an obvious and growing split between the poor working class, especially in rural areas and “flyover country”, and the wealthy urban liberals, and I suspect it’s fueling that anti-intellectualism. Higher ed is already viewed (not unreasonably!) as a hotbed of liberal culture and politics, and with scientific education available mostly to that set I can easily see how it could become politicized as a class and cultural marker.

        Dunning-Kruger also pokes its head in here; with falling educational quality, you’re bound to see a growing population of people who neither understand nor value science itself, and – having no perspective with which to evaluate competing claims – view internet crackpots and fraudsters as just as valid, or even better, since those distrusted institutions are presumptively wrong, and therefore you have to go to crackpots for the real facts.

        A critic might say that doesn’t explain the growing number of wealthy white antivaxxers, and you’re right, it doesn’t. I have no explanation for that, frankly; it baffles me.

  2. Michael says:

    Derek, you mention that J&J is the only one-shot candidate going through trials…have the AZ/Oxford team definitively ruled out a one-shot approach?

    1. Derek Lowe says:

      Not sure if they have, but they are definitely trying the two-shot as well. I think that J&J are the only group that isn’t even trying a booster.

      1. Duncan says:

        I had understood from the recent announcement in the UK that J&J were trying two doses as well as one.

        https://www.gov.uk/government/news/uk-government-secures-new-covid-19-vaccines-and-backs-global-clinical-trial

      2. Nate says:

        I’m in the AZ/Oxford clinical trial and they definitely told me to plan on two injections.

  3. Robert R. Fenichel says:

    A typo: “and toxi)” should be “(and toxic)”

  4. Barry says:

    Perhaps someone here can explain why inactivated virus vaccines tend towards protein denaturing agents (e.g. propriolactone) and not towards DNA/RNA breakers (e.g. UV) when the intent is deliver a natural-looking antigen protein) w/o an infectious polynucleotide message?

    1. MagickChicken says:

      Keeping an eye on this one, I’m also curious!

    2. Marko says:

      I suspect the main reason is that it’s much easier to treat a large batch of virus with a chemical agent than with UV.

      UV-inactivation has been used successfully to prepare SARS inactivated virus , but I’m not sure that this example really qualifies as “large scale” :

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122600/

      They mention 400 ml. batches uv-treated for 20 min. in flat containers such that the supernatant depth is less than 2.5 cm to allow sufficient uv penetration.

      1. Mammalian scale-up person says:

        You’d need some kind of material (most likely plastic) that UV can penetrate, but which can also be cleaned in place to a total organic carbon level BDL, and that can be sterilized in place, either with steam or VHP or one of the liquid sterilants, and which has no detectable extractibles and leachables. Not a lot of materials that fit those specifications, and UV embrittlement in plastics is an issue. The most intuitive design would be a bit like a pasteurization system: flow the material through long thin tubes to ensure exposure dose and time.

        Seems like some proteins can tolerate up to 25 kGy of gamma irradiation before they start to significantly degrade – why not try gamma? We know how to do the dosimetry, there are large scale facilities throughout the world.

        1. Barry says:

          fused quartz tubing is neither exotic nor particularly expensive. We use it in photochemistry apparatus routinely for all the reasons you enumerate.

        2. Chris Phoenix says:

          Serious-but-naive question here – in an apparatus designed to be flooded with UV to a level that reliably destroys even viral-length DNA, why would you need any other means of sterilization?

          1. Mammalian scale-up person says:

            You wouldn’t need UV at that point anymore whatsoever. Plus, a custom system is not only a lot of money but takes a very long time to build and validate. If you can use something that already has a good track record of FDA approvals, it makes life a lot easier. When you have to build anything custom, add at least a year, maybe 18 months.

  5. Alan Goldhammer says:

    The vaccine is being trialed in Indonesia, Brazil and I think also one Mid-Eastern country.

    1. Stephanus says:

      The one that is trialed in Indonesia is Sinovac’s vaccine..

  6. Giannis says:

    There is little reason to use inactivated viruses nowadays. We could easily create viruses that cannot replicate in human cells at all with the use of genetic engineering. Most of the vaccines that have led to disease enhancement are inactivated vaccines. The reasons are significant th2 polarization and formaldehyde/Propriolactone might lock the viral proteins in unwanted conformations. The failed RSV vaccine that killed ~20 kids was an inactivated vaccine.

    Of course everything might be all right since there have been no issues with NHP models…

    1. Marko says:

      The good news is that mRNA vaccines don’t have problems with disease enhancement. The bad news is that no mRNA vaccine has ever been approved for use.

      The math says that when inactivated vaccines have historically been the dominant class of vaccines approved for use in humans , that you would also expect that vaccine class to show the most examples of problematic outcomes , as well as successes.

      1. Whoa, there. You can’t rule out vaccine-enhanced severity for any of the current vaccine candidates until you have a large enough study population with sufficient length of follow-up to reveal difference in outcome from natural infection between immunised and control groups. Likewise, if vaccination cannot achieve sterilising immunity, then it will be a while before benefit through severity reduction becomes clear.

        1. Marko says:

          “Whoa, there. You can’t rule out vaccine-enhanced severity for any of the current vaccine candidates….”

          That was exactly my point , but perhaps my “good news/bad news” phrasing was too cryptic. We couldn’t expect mRNA vaccines to show evidence of disease enhancement because we simply haven’t looked for it yet.

          Inactivated virus vaccines have been used in millions , so if disease enhancement is a thing , it’s only natural that it would have showed up in that type of vaccine.

          There’s at least a theoretical argument that multi-epitope vaccines could be more problematic in this regard than those containing few epitopes , but I don’t think it’s been proven yet in human trials.

          1. Apologies for my misreading.

            As an aside, in the translational mRNA vaccine work up, MSD/Moderna did not find evidence of vaccine-enhanced severity in a cotton rat model, using a raft of constructs expressing native and mutated forms of the RSV F protein (the source of trouble in the formalin-inactivated vaccine studies).

            From limited example, hypersensitivity following vaccination seems to be linked to conformational change, either inactivation-induced in the case of RSV, or down to the expression system (observed with SARS, and possibly MERS, vaccines).

    2. Sc says:

      Pretty sure that rsv vaccine only killed two kids. Still terrible but an important difference.

      1. That’s correct, assuming you are referring to the formalin-inactivated vaccine studies from the early 60s. Hospitalisation rates were high across all studies, largely in younger infants. Studies with another FI vaccine conducted in the mid-60s had a low rate of adverse events.

        1. As a coda to my response, the Th2 mediated hypersensitivity response to the FI vaccine was eventually linked to changes in RSV proteins resulting from the inactivation process. Both formalin and heat inactivation result in irreversible transition from the prefusion to the postfusion conformation of the RSV F protein and loss of neutralising antibody inducing epitopes.

      2. Riah says:

        “Pretty sure that rsv vaccine only killed two kids. Still terrible but an important difference.
        Reply”
        Yes that’s correct but did you know that according to Dr Hotez (Baylor) they and the group they did the trials on were black? There were also many more that became seriously ill and were hospitalised. All hushed up, particularly because of the race issue (again from same source – an interview of Dr H) and we don’t know whether there were any long term effects.

  7. Stephanus says:

    Sinovac has also release their phase 2 trial data: https://www.medrxiv.org/content/10.1101/2020.07.31.20161216v1

  8. danS says:

    How are other flu viruses inactivated? Although chemicals are typically used I always thought it was a fairly trivial part of the process. I am surprised the timeline has been so long for the vaccine development and ther has been so much apprehension about possible side effects and vaccine effectiveness

      1. DanS says:

        Yes ADE is a remote possibilty and they really should do challenge trials on small group of healthy young people to see if this is really an issue. What are you going to do if you vaccinate 15,000 people in a phase 3 trial and find out that they have an enhanced susceptability to the virus and the vaccine provides no protection? Of course challenge experiments are unacceptable too as far as they are concerned. The risks are larger with this virus than say H1N1 because covid is so much more dangerous however the downside of being too cautious is 1000’s of additional lives will be lost. Finally some of the issues raised in the paper such as ADE in mutated H1N1 flu viruses will never be resolved in a phase 3 trial. They will only occur a few years down the road.

    1. Riah says:

      I have replied to this but it seems to be stuck in moderation. Guess Derek will release it in due course….

  9. Edward says:

    The frightening, bulging-eyed fanatical fervor of the “anti-vaxxers” is only matched by the frightening, bulging-eyed fanatical fervor of the “anti-anti-vaxxers”.

  10. idiotraptor says:

    Interestingly, the CDC website does not specify how influenza virus is inactivated in preparation for vaccines ( https://www.cdc.gov/flu/prevent/how-fluvaccine-made.html). I believe formalin treatment followed by dialysis is the method used for a number of commercial vaccines.

  11. DTX says:

    What is the basis that “most of the vaccines that have led to disease enhancement are inactivated vaccines”? Vaccines dot gov notes that the 4 available inactivated vaccines are: Hepatitis A, Flu (shot only), Polio (shot only), and Rabies.

    The first 3 don’t cause “disease enhancement” and I don’t know about whether the rabies does (I’ve never heard this).

    Notably, the world has mostly moved to inactivated polio because it is seen as slightly safer than live attenuated polio (because the latter can revert to wide-type and actually cause polio, albeit very rarely).

    1. Metaphysician says:

      I seriously doubt there is any such thing as ADE with rabies, seeing as ADE by definition involves disease symptoms worse than a zero antibody new infection. The symptoms of zero antibody rabies are “guaranteed agonizing death”. You can’t really enhance that.

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