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A Shot in the Dark
Actually multiple shots, not all vaccines
It would not have been foreseen that a vaccine directed to the original, ancestral SARS-CoV-2 strain would hold up so well against one that evolved over 2 years, after hundreds of millions of infections, to the hyper-mutated Omicron. But it did.
I previously reviewed the data for 3-shot vaccines reducing Omicron infections and transmission, albeit at a much lower rate than we had previously seen with prior variants. That falloff in preventing infections and transmission certainly helped promote rapid Omicron spread, with a virus that has intrinsic properties of hyper-transmissibility, to extraordinary and unprecedented levels across the world. In the United States, it is estimated that we’ll have 36-46% of Americans infected with Omicron by mid-February 2022.
The Dichotomy of Protecting From Infections vs Severe Disease
Fortunately, the reduction of 3-shot vaccine prevention of infection by 50% or less is dramatically different than the prevention of death and hospitalization. There are several new data sets to review that provide an exceptionally favorable outlook. Let me summarize in this Figure the data for vaccine effectiveness vs Omicron for 2 and 3 shots
Notably, we had the first readout from the UK for reduction of Omicron deaths for vaccines by the UK Health Security Agency and the 95% vaccine effectiveness vs death (95% CI 90-98) is striking for 3-shots Only 59% for 2 shots, waned.
Previously, we’ve seen the data for vaccine protection vs Omicron hospitalizations in 3 reports, the UK, Kaiser Permanente, and CDC, summarized here. Also note that there was durability of protection for at least 3 months in the 2 reports with follow-up data.
This past week the CDC came out with new data that are quite impressive for vaccine effectiveness for both death and hospitalization.
Death was reduced by 99% overall and across all adults age groups for 3-shots, something I first noted and was surprised this was not a main message disseminated by the CDC. Fortunately, Edouard Mathieu at Our World in Data also recognized its importance and replotted my makeshift graph that I originally posted on twitter. These data are from the Delta wave, but we already have data from the Omicron wave in the UK to substantiate an extremely high level of protection. Notably, the 99% reduction of death was remarkably similar to the data from Switzerland, where there were no deaths with 3-shots for anyone less than age 70.
Here are the parallel data for Switzerland. The 7-13 fold further reduction of death from 2 to 3 shots in both countries deserves to be highlighted. There aren’t such data available for other countries yet, except for Chile, which had 94% reduction of death with 3 shots, and used Sinovac vaccines in >75%.
The new CDC data for vaccine effectiveness vs hospitalization during the US Delta wave are quite impressive, too. A 98% reduction for age 65 and over, and a 97% reduction for age 50-64. The unvaccinated data in the graph compressed the very significant difference between 2 and 3 shot reduction, which is discerned by looking at the absolute numbers here and on the interactive graph provided by the link.
In aggregate, these data sets provide overwhelming evidence for the original vaccines, with a 3rd shot, giving us a remarkable level of protection from need for hospitalization and death. Since Omicron is characterized by less severity, as evidenced many ways including by less ICU admissions (except in the United States, which we’ll get too shortly), the relative reduction might be expected to be somewhat less, yet thus far the difference has been minimal.
History Will Not Be Kind to the United States Pandemic Performance
It might not have been anticipated that the country—which developed and manufactured the mRNA vaccines and did the pivotal clinical trials that showed 95% effectiveness vs symptomatic infections—would rank below 60 among countries for vaccinating its people or have a particularly poor showing for getting 3rd shots compared with many European, South American, and Asian countries. But is has been frankly pathetic, largely a function of aggressive mis- and dis-information campaigns by anti-vaxxers and the politicization of vaccines (along with masks and other mitigating measures). Here’s a comparison with 6 European countries during the Omicron wave. You’ll note the US has suffered 2-7 fold more deaths, 2-8 fold more hospital admission per capita, which coincides with a 10-20 per cent absolute gap in 2 shot vaccination and up to 65% less booster rate. I’ve already stressed the vital need for the 3rd shot to reduce Omicron deaths and hospitalizations.
If we just look at the United States outcomes, it is notable that hospitalizations reached a new peak of near 160,000, by far its highest, and deaths are now averaging over 2,500 per day with multiple recent days approaching 4,000, and the death rate is still rising sharply, already surpassing the peak of 3 of the prior waves.
It is clear to me that some of the pronounced rise in hospitalizations and deaths could have been reduced by an early and aggressive booster campaign, but recall that the CDC did not endorse 3rd shots for all adults until November 29th, after Omicron was recognized, even though the data for their protection versus severe disease was abundantly clear in August from Israel (vs Delta) and confirmed in multiple data sets including a >10,000 participant randomized trial of 2-shots + placebo vs 3-shots which showed 95% effectiveness vs symptomatic infections for the latter, across all age groups.
In a matter of days, the United States will reach the ignominious number of 900,000 confirmed deaths, more than half of which occurred well after vaccines were widely available to high risk (by age or immunocompromised) status. It is now inevitable that we’ll soon see that toll rise to more than a million American lost lives, and we know that well over 90% of these deaths were preventable with vaccination. The actual number of deaths by excess mortality calculations already exceeds 1 million in the United States
I’ve reviewed 2 shots in the dark so far—the surpassing level of protection of vaccines with a 3rd shot against Omicron for severe disease, and the continued, unexpected poor performance of the United States in managing the pandemic. Now we’ll turn to a third shot—the potential need for a 4th shot. That wasn’t supposed to be needed, at least at a time just 4 months later.
The Fourth Shot Question
On January 23, 2022, for the Omicron wave that hit the country exceptionally hard, the Israel Ministry of Health presented their data for 400,000 people age 60+, health care workers, and other high risk individuals who had a 4th shot compared with about 600,000 people who had 3 shots and were at least 4 months out from their last vaccine dose. There was a >3-fold increased protection vs severe disease, “a triple protection against hospitalization and double resistance against Omicron infection.” That’s all the data we have so far, but why is this so surprising?
As I’ve reviewed in prior posts, the memory B and T cell response has far more plasticity than neutralizing antibodies for dealing with Omicron. We’ve already seen the 3rd shot data protection for Omicron and it’s quite strong versus severe disease, approximately 90% vs hospitalization, 95% vs death. So why would there be a 3-fold or more protection after waning of the 3rd dose?—that wasn’t supposed to happen. Recall that our on-demand T cells would be expected to kick in, recognizing Omicron fairly well, and even though delayed as compared with neutralizing antibodies, take down the virus and prevent Covid pneumonia, no less other organ disease. The 3rd shot was anticipated to be quite durable and not exhibit a waning pattern, which has thus far largely been correlated with neutralizing antibodies. Israel’s advisors have suggested that 4th shots should be given to all adults, although the only supportive data to date are for the age 60+ (and “high risk) group. It is also contextualized by Israel having a remarkably high level of circulating virus in their Omicron wave, by far the highest cases per capita, and setting a new precedent in the world with a. 7-day new case average ~11,000 per million people. The reason for this disappointing and somewhat surprising finding in Israel requires definition as to why the cellular immune response did not provide a high level of durable protection against Omicron.
Predicting the Pandemic
The next shot in the dark that I’ll mention is about projecting about the next phase of the pandemic. My colleague, Kristian Andersen at Scripps Research (and parenthetically one of my top recruits in my career), put it well on twitter
In one form or another, SARS-CoV-2 will be with us for many years ahead, and it’s up to us to contain it with the tools that we have now and those in the future, including increased availability of anti-Covid pills (see prior post on Paxlovid) , better and ideally variant-proof vaccines, such as those which may achieve mucosal immunity and block transmission (see Akiko Iwasaki’s group recent report), pan-sarbecovirus vaccines, and improvement in mitigation measures like routine air filtration. All this exciting biotech stuff will not substitute for the vital need of getting on board as many of the 3 billion people around the world who have not been vaccinated. While we just reached 10 billion dose of vaccines administered this week, a stunning human achievement in about 1 year, the maldistribution around the world, especially so little in Africa, is going to hold us back from achieving global containment.
P.S. Last shot, directed at Substack
Perhaps you’ve read the Guardian piece on the anti-vaxxers, such as Alex Berenson, Robert Malone, Joseph Mercola and others, who have a major presence on Substack and are making large amounts of money via subscriptions. Before that piece arrived, when I first posted on Substack in December, some of these individuals organized a vicious, ad hominem attack through comments on my welcome post that necessitated me taking down the comment section. That was a big disappointment for me, since I had agreed to an experiment at Substack as a writer-in-residence to get constructive comments and exchange ideas.
I subsequently had a lengthy discussion with Hamish McKenzie and Chris Best, co-founders of Substack. While I am fully supportive of freedom of speech in general, I strongly believe that a line must be drawn when lies, distortion, and fabrication are leading to serious illness and deaths. That is why I joined the open letter to Spotify about Joe Rogan and why I applaud Neil Young and Joni Mitchell’s efforts. I remain upset and quite dismayed that Substack’s founders have decided not to recognize this—a lack of tolerance for freedom of speech when it adversely and significantly impacts public health—in their recent post expressing unwillingness for censorship of any kind.
For the time being, I will continue to post on Substack as I believe there’s a serious lack of ground truths about the pandemic. I’m not sure how long that will continue; I’ll be reflecting on whether this platform is a suitable channel for writing such posts.