Provided One Chooses the Right (wrong??) Conditions, Many (any?) Spike Protein-based Covid-19 Vaccines May Prevent Transmission of SARS-Cov-2 Variants

Introduction:

The study referred to in the link below proposes the use of yellow fever as viral vector for an updated S-based Covid-19 vaccine (YF-SO*) to illustrate that “adaptation” of first generation COVID-19 vaccines could allow C-19 vaccines to stay ahead of the virus.

Updated vaccine protects against SARS-CoV-2 variants including Omicron (B.1.1.529) and prevents transmission in hamsters | Nature Communications

There is only one problem: The model is completely irrelevant as it does not apply at all to the current situation of the C-19 pandemic, i.e., highly vaccinated populations. Regardless of the nature of the preclinical vaccine candidate, no single challenge experiment using obsolete SARS-CoV-2 variants in previously immunologically naïve, non-hACE2-transgenic hamsters that are intraperitoneally vaccinated with S-based SARS-CoV-2 (SC-2) vaccines allows for the drawing of any relevant conclusion for vaccine use in humans during this C-19 pandemic, regardless of the vaccine platform used for delivery of spike (S) protein and possible updates/ adaptations of S protein to the circulating variants.  

It is interesting to see how researchers are now jumping on updating S protein in their favorite vaccine constructs. Why would one think these constructs are any better than the previous ones harboring the ancestral S protein? Booster doses with the original Wuhan-Hu S-based C-19 vaccines have repeatedly been claimed to induce broadly neutralizing antibodies (Abs) in the human target population and even to provide protection from Omicron (sub)variants. It was therefore not deemed necessary to update Covid-19 vaccines to control viral transmission and protect from C-19 disease. However, the duration of immune protection conferred by C-19 vaccine boosters rapidly declined. As the duration of protection conferred by booster doses of other ‘updated’ S protein-based C-19 vaccine candidates is fully unknown, it is questionable whether they can outperform the first generation C-19 vaccines. This already indicates that claims for the need of updated SC-2 variant-adapted C-19 vaccines to improve protection lack credibility, especially when tested in irrelevant animal models. At the very least, one would expect that experiments conducted on such updated candidates demonstrate sustained protection, especially when candidates aim at preventing viral infection/ transmission to end the C-19 pandemic! The study I am referring to does not provide such data. This element already questions the credibility of the alleged need for “updated” S-based C-19 vaccines as postulated by the authors.    

Irrelevance of the animal model and neutralizing Abs (NAbs) as correlate of efficacy/ protection

The authors acknowledge that the model is not suitable for assessing the infectiousness of Omicron B.1.1.529. They also understand that hamsters which do not express the human angiotensin-converting enzyme 2 (ACE-2) receptor may not even be suitable at all for studying SC-2 infectiousness as SC-2 specifically binds to the human ACE-2 receptor through its receptor-binding domain (RBD), whereas human proteases specifically serve as activators of viral entry into human cells. Nevertheless, the authors seem to suggest that protection against infection from more recently emerged SC-2 variants (e.g., Omicron B.1.1.529) can be inferred from vaccine-induced seroconversion to measurable NAb titers in these very hamsters (i.e., in only 60% of the animals), whereas this correlate does not apply to humans. It has, indeed, become obvious that C-19 vaccines still protect vaccinees from severe C-19 disease (and even from C-19 disease altogether), whereas new emerging Omicron descendants are largely resistant to the vaccine-induced, potentially neutralizing Abs.  It would therefore be totally incorrect to even suggest that some correlate between NAb seroconversion and vaccine efficacy as observed in this study on hamsters also applies to human populations, including those that are highly vaccinated.  

Irrelevance of the SC-variants and the immune status of the animals tested in this model

Even if the model were suitable for Omicron B.1.1.529, the latter variant has become obsolete as it has been replaced with Omicron descendants exhibiting very different phenotypic characteristics, not only regarding their enhanced resistance to NAbs (even including broadly NAbs), but also in terms of their enhanced intrinsic infectiousness. Newly emerging Omicron-derived (sub)variants are highly infectious and hence, animal models that are scarcely susceptible to infection with Omicron B.1.1.529 are unlikely to have any predictive value in regard to viral transmissibility of yet another, even more infectious generation of Omicron descendants that are currently co-circulating.

It also goes without saying that preclinical experiments in animals that do not serve as a natural host to SC-2 have no predictive value for humans, even though they allow for detection of differences between distinct C-19 vaccine constructs. The authors think this issue could be resolved by repeating this type of experiment using hACE-2 transgenic hamsters. But even if hACE-2 transgenic hamsters were used, the results would still be irrelevant to the current C-19 pandemic, since the overall preclinical setting ignores the impact of pre-existing vaccinal Abs. It has been shown, for example, that viral infectiousness of SC-2 variants is particularly enhanced in animals harboring pre-existing vaccinal Abs with substantially reduced neutralizing capacity (resulting in stimulation of infection-enhancing Abs) as extensively documented by Prof. J. Fantini at Aix-Marseille Université in France (https://pubmed.ncbi.nlm.nih.gov/34384810/).  
Furthermore, the study setting also fully ignores the potential impact of immune imprinting and immune refocusing. It has been extensively documented that these phenomena can occur upon re-vaccination (i.e., administration of vaccine booster doses) as well as upon vaccination in the presence of pre-existing Abs from natural infection. Given that this results in re-orientation of the immune response, immune imprinting and, more generally, immune refocusing are currently responsible for exerting suboptimal immune pressure in highly vaccinated populations and driving convergent evolution of immune escape mutations to more conserved S-associated domains (whereas pre-Omicron variants exhibited convergent evolution in variable S-RBD domains). In addition, recent results from updated Omicron vaccines have shown no benefit in comparison to the original Wuhan-Hu-based C-19 vaccines, an observation that is also thought to be due to immune imprinting (https://www.cnbc.com/2022/10/27/new-covid-booster-shots-dont-protect-better-against-omicron-bapoint5-studies-find.html). So, it is not reasonable to downplay the issue of ‘original antigenic sin’ by qualifying the issue as ‘unclear’ (“It is hence not clear whether or not novel variant-proof vaccines will suffer from relatively poor variant-specific NAb booster responses”).

Irrelevance of route of injection

No vaccine for human use is administered via the intraperitoneal route. Not only does this type of administration prevent any prediction in regard to potential local reactogenicity in humans, but it can also elicit a stronger systemic NAb response and have great variability in effectiveness. There is no reason to not use routes of injection in hamsters that are routinely used in humans (e.g., IM, SQ or intradermal) unless vaccine researchers want to avoid (hide?) problematic local reactogenicity.  

No evidence of durable protection

Although the viral challenge experiments illustrate the added value of the updated S-based vectorized vaccine, no data have been provided on the longevity of this response. Structural changes in the S protein that result from stabilization of S protein in the pre-fusion conformation are known to enhance immunogenicity. However, one cannot rule out that stabilization enables exposure of immune subdominant domains. The latter are known to induce Abs that have a broader spectrum of neutralization but with much more limited longevity. It would therefore be critical to investigate the duration of broadly cross-reactive immune responses induced by so-called “updated” C-19 vaccine boosters tested in a relevant preclinical setting. Vaccines that elicit protective immune responses which rapidly decline are of no practical use and undoubtedly increase the risk of promoting immune refocusing due to breakthrough infections.

Lack of adequate controls

Given the short interval between the immunization and exposure data (3 weeks), it cannot be ruled out that trained innate and not adaptive immunity was responsible for curtailing viral transmission to the non-vaccinated sentinels during close contact. It is well known that live attenuated viruses train innate immunity and can thereby eliminate most – if not all - of the viral load. Without an appropriate control (e.g., the YF vector without S protein), it is impossible to evaluate whether vaccine-induced adaptive immunity is required to prevent viral transmission. And even if the adaptive immune response contributed to this protection, the question regarding the duration of this adaptive immune protection remains (see also above).

Why even use yellow fever virus as a vector for spike protein?

Notwithstanding the irrelevance of the preclinical model used in this study, one wonders why researchers are using live attenuated Yellow Fever (YF) virus as a vector for S protein. This not only raises questions regarding the risk of lack of “vaccine take” in individuals with pre-existing Abs against yellow fever (e.g., as because of previous YF vaccination or use of YF-vectorized vaccines) but also in regard to safety. The latter particularly applies to the elderly and to people with a weakened immune system (e.g., due to co-morbidities). These subjects are clearly considered the key target population by those who still believe that C-19 vaccines can tame the current pandemic and/or continue to protect from severe C-19 disease.  

In conclusion: Although preclinical settings that are not representative at all of the evolutionary dynamics of the virus or the immune status of the population may suggest a beneficial effect of updated C-19 vaccines, there can be no doubt that no single “adapted” S protein-based C-19 vaccine (including chimeric constructs) will be able to yield neutralizing Abs capable of “staying ahead” of the ongoing explosion of Omicron-derived variants.

Because of immune imprinting combined with immune refocusing, booster shots with updated mRNA-based Omicron-adapted vaccines have failed to meet the expectations of improved neutralization of circulating Omicron-derived variants. Regardless of these unsurprisingly disappointing results, breakthrough infections in vaccinees or post-infection C-19 vaccination has been shown to drive immune targeting away from the immunodominant S-associated epitopes. Vaccine researchers still don’t seem to realize that any C-19 vaccine that falls short of preventing viral transmission when deployed during this pandemic will only join the long list of “me too” vaccine candidates, that eventually end up promoting immune escape and further enhancing the currently observed escalation of SC-2 infection rates.

It is therefore fair to conclude that the updated SC-2 vaccine construct tested in this study is unlikely to reduce viral transmission when tested under real life conditions (i.e., during this pandemic). The results of the model used in this study are therefore misleading and raise unreasonable expectations that updated booster doses will help tame the pandemic and/or maintain protection against severe Covid-19 disease. Unless protection data generated in a relevant preclinical model proves the opposite, there is no foundational scientific basis to assume that updated C-19 vaccines, including the type of construct proposed by the authors, will be able to catch up with the evolutionary dynamics of SC-2 in highly vaccinated populations. On the contrary, there is now growing compelling scientific evidence that updated booster doses will only accelerate the emergence of additional mutations instead of “covering” them as the authors claim. As I always say:  Africa will win this battle!