Catching up with COVID?

The new COVID boosters targeting BA.4/.5 will be rolling out as early as next week. After a year and a half of having only the original vaccine to combat a parade of variants with increasing vaccine escape capacity, this should be a step forward. How much of a step will depend on the new boosters efficacy, and perhaps more importantly, on their reception and uptake by the population. The latest CDC statistics show that only 34% of eligible people in the US have had at least one booster. That means that an enormous number of people, who bought into initial vaccination, did not sign on for a booster. These are not “antivaxers” with a deeply rooted distrust of the general concept — and to account for this dismal percentage they must span the political, racial, and socio-economic spectrum. I could imagine that all the reasons which have been cited at one time or another are operative: poor messaging and promotion by the CDC, from the beginning, regarding the benefit of boosters, unpleasant side effects, the realization at a personal level that boosted acquaintances are coming down with COVID. I can speculate that perhaps the most significant reason is the very success of the vaccines in reducing the severity of disease, and consequently altering the perceived risk. The average person who might have some reservations about the vaccine would have been more likely to take it when the perceived risk was greater, and the daily death count was broadcast on the nightly news as a “new grim number”.

Efficacy of the new boosters versus a boost with the original vaccine is likely marginal at best. Antibody levels against BA.5 in the test subjects (who were all of the rodent persuasion) were only 1.8-2x higher than what was achieved by boosting with the original vaccine. At a clinical level that may equate to a slightly better protection from infection, but there is no reasonable hope this difference will dramatically impact the ongoing transmission of the virus. Here in the US, we have now had a continuous period of 4 months with daily deaths ranging from 300-500/day, and although slightly lower in the last 2 weeks, we still have 30,000 hospitalized with COVID. Elderly people over 70, those who are significantly immunocompromised, and those with severe medical co-morbidities need to maintain antibody titers sufficient to protect against severe disease, and that requires boosting with the current mRNA vaccines. (That does not take into account natural boosting created by a recent infection in the Omicron era). The open question in my mind is whether a very marginal improvement in vaccine performance will be offset by the negative impression that these new BA.4/.5 boosters were rapidly developed without human efficacy or safety testing. I have a hard time imagining people who opted to avoid taking a booster during the previous periods of tremendous disease surges and deaths suddenly thinking, “I’ve got to get me some of the new BA.5 stuff”. On the other hand I can envision SOME previously boosted folks being leery of the new formulation. I am reminded of the words of a prominent politician leading up to the release of the original vaccines, “If these vaccines are released before election day, they have been rushed and not adequately tested, and you shouldn’t take them”. The most perfect vaccine is only as good as the number of people who take it, and that number is highly influenced by the confidence communicated by the government. One further point on the new boosters. Two versions were tested; a monovalent designed around BA.5, and the bivalent with both BA.5 and original Wuhan. The FDA opted to go with the bivalent, but reasons for that are not clear. The data submitted by Pfizer and Moderna show higher NAB (neutralizing antibody) levels were generated by the monovalent BA.5 version against not only BA.5, but also against all the other variants tested. The logic of including the Wuhan antigen, in view of this data frankly escapes me— we don’t need further imprinting of our immune systems to a now extinct virus.

On the issue of mRNA vaccine side effects, there is a recent study out of France giving us further very encouraging data on a lack of serious cardiovascular events. We have had data for some time showing the mRNA vaccines did not cause any significant increase in MI, PE, Stroke and CV death in the over 75 yo group. The new French study shows that in the 18-75 yo group of all French citizens receiving the Pfizer or Moderna vaccines, there was no significant measurable increase in these critical events. The same cannot be said of the Adenoviral vaccines (AstraZeneca-Oxford and Janson), and an association with thrombotic complications was recognized early on. (This current French analysis does not include myocarditis/pericarditis events, which I discussed at length in earlier issues of this news letter: The FDA Provides Further Information on mRNA Vaccine Risk, April 2 ) Below is the link to this paper.

https://www.acpjournals.org/doi/full/10.7326/M22-0988?af=R

Under the assumption that the relationship with MI and PE is causal among persons who received the Oxford–AstraZeneca vaccine, 22% (CI, 10% to 34%) of MI events within the second week after the first dose were attributable to the vaccine, corresponding to 1.3 events per 100 000 doses. Similarly, 29% (CI, 12% to 43%) of PE’s within the second week after the first dose were attributable to the vaccine…. The incidence of MI was increased during the second week after vaccination with a single dose of the Janssen vaccine compared with control periods, with an RI (relative incidence) of 1.75 (CI, 1.16 to 2.62). Under the assumption that the relationship is causal, 43% (CI, 14% to 62%) of MI events within the second week among persons who received the Janssen vaccine were attributable to vaccination, corresponding to 2.4 events per 100 000 doses.

Next is the geeky science part. Everybody who follows these pages or Dr. Eric Topol’s substack knows that the holy grail in COVID vaccine development is reasonably focused on development of topical nasal vaccines, that may have the potential of much more effectively blocking infection in the first place. Another avenue is searching for improved adjuvants, or the ingredient in a vaccine which attracts the immune system, and up regulates its response to the target protein. For anyone interested some basic vaccine research, I offer the following intriguing paper. The necessary background is that your immune system, when confronted with a new, never before seen invader, makes antibodies against many different areas of the protein (called epitopes). Many of these antibodies don’t contribute to neutralizing the virus or bacteria and preventing infection. These researchers identified one of the sites in the receptor binding domain of the Wuhan spike protein which is immunodominant, and triggers formation of many of the non-neutralizing antibodies. They “covered” this site on the protein by adding a type of sugar molecule to it (glycosylated the site) and then compared the result of vaccinating mice with the original Wuhan protein, versus the altered spike. The altered protein caused the mice to produce significantly higher NABs against not only Wuhan, but against a whole panel of variants including Alpha, Delta Epsilon and Omicron—with significantly increased protection of the mice from a lethal dose challenge of Delta variant. (Delta was particularly nasty for both Mice and Men). This demonstrates that the immune response can be creatively focused toward more effective neutralizing antibodies.

A Glycosylated RBD Protein Induces Enhanced Neutralizing Antibodies against Omicron and Other Variants with Improved Protection against SARS-CoV-2 Infection. DOI: 10.1128/jvi.00118-22

Monkeypox case growth has slowed around the world, and in the US newly reported cases decreased by 20% in the last week. That is extraordinarily good news, and suggests the virus is giving way to vaccination efforts, and positive changes in behavior within the high risk demographic. The reports of some cases from college campuses is concerning though, and may presage a new direction for spread during the fall. Hopefully we will be able to see data emerge quickly on vaccine efficacy and on prevention of asymptomatic carriage. More locations, primarily metropolitan, are coming onboard with waste water testing for the virus and that should be a valuable tool for judging the amount of both symptomatic and asymptomatic disease in the community. Without waste water testing, we are dependent on random rectal samples (likely to be about as popular as root canal) to assess the frequency of asymptomatic carriers, perhaps capable of spreading the disease.

As we head into the autumn we should expect an uptick in COVID disease. Since the population seems to have accepted the current level of illness and death as the new set point for “living with COVID”; and since the government has taken a vaccine centric approach to controlling disease, and devolved essentially all other mitigation options to personal choice, this seems unavoidable. The good news for right now is that no significant variant challenging the primacy of BA.5 has appeared so far. I will leave you with a quote from Gary Kasparov, a citizen of the USSR, with some knowledge of such things.

The point of modern propaganda isn't only to misinform or push an agenda. It is to exhaust your critical thinking, to annihilate truth.

Enjoy the end of summer holiday and don’t let anyone do your thinking for you.