As with previous such reports, comments must be caveated on the basis that we are seeing a press release, not a formal scientific presentation on the trial’s findings.

The Valneva vaccine is a much more “traditional” or familiar type of vaccine than the vector and mRNA vaccines that were first to market for Covid-19.  The vaccine uses inactivated SARS-CoV-2 virus particles as the antigen.  (In contrast vector and mRNA vaccines introduce genetic code into cells to induce the production of proteins identical to the virus’ spike protein.)

As the whole virus is used (after inactivating or “killing” it so that it cannot cause disease), this vaccine will contain antigens – parts of the virus – that are not included in vaccines which only produce spike protein.  This has the potential, in turn, to lead to broader immunity, as mutations in the virus’ spike protein could, theoretically at least, lead to “immune escape variants” arising; whereas a vaccine which also contains other parts of the virus might continue to be effective.  (That said, however, we have seen very little reduction in effectiveness of mRNA and vector vaccines due to viral variation: it may be that the level of mutation that would be required to evade the immune response would reduce the virus’ ability to attach to and infect cells.)

The study compared Valneva against AstraZeneca’s AZD1222 (ChAdOx1-S) vaccine; so we can compare the two vaccines directly.

Compared to some of the other phase 3 trials, this one had relatively few participants: only about 4,000, compared to nearly 24,000 for the AstraZeneca vaccine1, and over 43,000 for the BioNTech vaccine2, for example.  This will have reduced the power of the trial, and its ability to detect uncommon adverse reactions.  However, by comparing the efficacy of the vaccine against a comparable vaccine, the reduction in power is likely to be less significant than if it were being compared against a placebo: others will be better placed to comment on this than me.

mRNA and vector vaccines seem to be a bit more reactogenic (causing local reactions and transient symptoms such as fever and headache) than traditional vaccines, so it is reassuring, but was no surprise, that the Valneva vaccine appears to be less reactogenic than ChAdOx1-S.

In terms of laboratory assessment of efficacy, Valneva produced higher levels (as measured by geometric mean titre, “GMT”) than ChAdOx1-S.  The clinical and epidemiological significance of this has yet to be seen.  In terms of preventing infection, you need enough antibodies; the benefit of additional levels of antibody is more in terms of the expected duration of protection.  If there is a threshold level above which you are protected, the higher the level induced by vaccination, the longer it is likely to be (since antibody levels decay in an approximately linear way) until you lose immunity to infection.

Even if you can still be infected (because of waning antibody levels), you are very likely, if the vaccine induced cellular immunity and immune memory, to remain protected against significant disease – even (as we see with e.g. Hepatitis B infections) if antibody levels were undetectable prior to infection.

Nevertheless, the higher antibody levels induced might increase the period in which people are less likely to be infected, and thus, to be infectious and to infect others.

The Valneva vaccine was also shown to induce good cellular immunity, suggesting that it is likely, like the other vaccines we use, to provide good long-term protection against significant disease; and for Valneva, this cellular immunity was also raised against various non-Spike proteins.

ChAdOx1-S vaccine is known to be effective against cases and (more so) against severe disease.  I cannot find detail in the press release or presentation on the actual numbers; but I am prepared to believe that both vaccines were comparable in this respect.  We cannot tell from the data presented whether Valneva was differentially effective at preventing serious disease, hospitalisation, or death, because there were no serious cases of disease in either the Valneva or ChAdOx1-S group (presentation, p15).  (This was not, in any case, one of the study outcomes, so I am not clear why it was mentioned in the presentation.).

If Valneva is approved, we will start to see a lot more detail on its real-world benefits.  We will learn more about its effectiveness against a wider range of endpoints (e.g. asymptomatic infection, minor disease, serious disease, hospitalisation, critical care, and deaths).  We cannot rule out unexpected adverse reactions; but on the other hand, there is no reason to expect these to be any more significant than with other vaccines (although the relatively small size of this phase 3 trial means we are less confident of this than we might be).  Our vaccine adverse event detection systems have shown themselves to be very effective with the vaccines already on the market, so we can be confident that if there are such uncommon and unexpected adverse reactions, we are likely to detect them fairly promptly.

The good cellular immune response, and the response to antigens other than the spike protein, suggest that Valneva might provide a broader immune response, better able to protect against current and future variants of the virus; but, if this is the case, it will take some time for evidence of it to accrue.

I note that “The Company is preparing for trials in children (5-12 years of age) and a Valneva sponsored booster trial to evaluate VLA2001’s booster performance for people in need of a booster”.  (There is already some data on the vaccine’s efficacy in 13-17-year-olds.)  As I have speculated elsewhere, although the vaccines have, so far, proven far more effective that we could have dared hope this time last year, I think that, as the dust settles, it is likely that the vaccination regime will become (as it is for many other disease) a three-dose primary course, with occasional boosters (depending on the post-vaccine epidemiology)3.  Data from these additional trials will provide evidence for Valneva’s value as a third dose (whether you call it a third primary dose, or an early booster dose) and, possibly, for future, later boosters.

1 Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021. (https://doi.org/10.1016/S0140-6736(20)32661-1 or https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext).

2 Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020;383(27):2603-2615. (https://www.nejm.org/doi/full/10.1056/NEJMoa2034577).

3 English PMB. What will Covid-19 vaccination programmes look like in the future? Peter English’s random musings [blog]. Selected Covid-19 vaccine Q&As 2021; Updated 16 Oct 2021; Accessed: 2021 (16 Oct): (https://peterenglish.blogspot.com/2021/10/what-will-covid-19-vaccination.html).

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How does this trial differ from the earlier vaccine trials – was there a placebo, and if not does that mean we can directly compare this vaccine to the AZ vaccine, or not?

This trial was planned to look at what are called the immune responses to this vaccine, compared with those same responses to the Oxford-Astra Zeneca vaccine.  The comparison was not intended to be using symptomatic disease as the outcome studied.

It did not have a placebo group, since it would no longer be regarded as ethical to leave people un-vaccinated while the virus is still circulating.  It is a direct comparison to the AZ vaccine but the main outcome studied is not what the much larger trials of the AZ vaccine studied as their main outcome.  When there were no vaccines known to be effective in the earlier stage of the pandemic, it was vital that placebo or other controls were used, and the outcome studied had to be something like symptomatic disease.

What are the outcomes looked at here, and how does this compare with real-world outcomes like infection and disease?

Here the outcomes that have been looked at are related to antibodies measured in the blood of those participating in the trial.  With the knowledge we now have from earlier vaccine trials, we can be reasonably sure that the level of antibodies measured will predict, though with some uncertainty, the level of protection from infection and clinical disease.  The trial would have to be extremely large to show protection from infection or hospitalisation when compared with an already effective vaccine.  It could be argued that having such a large trial would be unnecessary when we know that the level of antibodies can predict clinical effectiveness.

We do not know the numbers who were infected with COVID-19, but the results apparently are similar to those with the AstraZeneca vaccine, but with a small trial any small difference is unlikely to be detected.  We do not yet know whether in clinical terms this vaccine is as good as, better than, or worse than AstraZeneca, but the immune response data suggest that it will be at least as good and probably better in clinical terms.

How does this type of vaccine differ from the COVID vaccines we already have?

This vaccine is more like conventional vaccines for diseases like flu then the vaccines like the AstraZeneca and the Pfizer or Moderna vaccines.  It was quicker to develop those vaccines which trained the body’s immune system to respond to the virus by just using a small part of the virus.  This vaccine from Valneva uses the whole virus, but it is inactivated so that it cannot cause disease in those receiving it.

Do we know whether this type of vaccine might be useful in terms of future variants if it’s a whole-virus vaccine, or don’t we know?

This vaccine although not specifically targeted at the delta variant was tested when the delta variant was dominant.  It is possible that by using the whole virus this vaccine might be more useful against future variants but we do not know this for certain.

Do we still need more new vaccines either for the UK and/or globally?

This vaccine seems to cause less immediate reactions to the injection then the AstraZeneca vaccine.  This may enable some people to have the vaccine who might not have had the other vaccines that are currently available.  We do still need more new vaccines especially for the rest of the world different vaccines have various characteristics that make them more or less useful in different settings.  Having a range of different vaccines with different properties will be helpful.

What are the storage requirements for this vaccine – might it be more easily used in the developing world than some other vaccines, or not?

It is likely that the requirement for refrigeration of this vaccine will be similar to that of other vaccines for other diseases and that this would make it more easily used in countries with less access to very cold refrigeration.

What would be the next steps in the process – would it be seeking MHRA approval or the equivalent in other countries?

The next steps will be seeking UK MHRA approval and this process is currently ongoing.  The following steps will be to obtain approval in the European Union and then in other countries.

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Valneva have issued a press release containing information on the immunological response to their inactivated protein vaccine, compared to response to the ChAdOx01 vaccine in a phase III trial conducted in the UK.  The trial uses an ‘immunobridging’ design which compares the immune responses to the two vaccines as a surrogate marker for clinical efficacy.  This is a well trodden path for vaccine development when new vaccines are developed for diseases in which clinical effectiveness has already been demonstrated.  In these circumstances comparison of the new vaccine to an already approved vaccine is required.  In this instance, the clinical trial, which was conducted in the UK, compared the inactivated adjuvented Valneva vaccine to Vaxzevria, the Astra Zeneca-Oxford vaccine.

As the results have been shared in the form of a press release, detailed information is not available, but based on the data provided it is reasonable to expect that the Valneva vaccine will be at least as effective in clinical use, perhaps more so if the apparently superior immune response is sustained across all patient groups, including the elderly and immune compromised.

An advantage of the whole protein approach is potential for sustained efficacy against emergent virus variants, although no information has been provided to enable this to be assessed.  The vaccine was reported to be well tolerated with fewer systemic reactogenic effects noted in recipients than following Vaxzevria.  It is a shame that the company elected not to compare this vaccine with the mRNA vaccines, although the difficulty of blinding the trial when one vaccine has to be stored in a freezer is acknowledged.  Now they have more data, perhaps the company will compare immune responses in an open label investigation.

Valneva produces this vaccine in a factory in Scotland and manufacturing of market supplies began in January.  It is stable at refridgerated temperatures, which is a good fit for established vaccine supply chains internationally.  As we know the UK government is in dispute with Valneva having cancelled the UKs order of up to 100million doses, placed by the Vaccines Taskforce in 2020, in September.  The results today suggest that this decision might yet be regretted, but because of it Valneva might be able to provide an immediate supply of this vaccine for other countries struggling with the freezer shipping requirements of other, more expensive, vaccines. Good news for Covax and countries still awaiting supplies.

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