Ground Truths on Prior Covid
How failure of the United States to acknowledge the evidence has unnecessarily fueled divisiveness and a war against mandates
Last week, a physician wrote a piece in The Lancet entitled “Health-care workers recovered from natural SARS-CoV-2 infection should be exempt from mandatory vaccination edicts” Dr. McGonagle pointed to multiple studies showing Prior Covid provides equivalent or better protection from vaccination, such as one study showing a 10-fold less likely for people with prior infection than vaccinated among >52,000 Cleveland Clinic employees (adjusted hazard ratio 0.02 vs 0.26). For symptomatic infection, that advantage was no longer present, as seen in the graph below, but prior to the Omicron phase (which we’ll get to later), there was a paucity of symptomatic infections among these health care workers who had Prior Covid. Notably, this is a physician writing to assert the protection by Prior Covid and against vaccine mandates, not the truckers protesting against mandates in Ottawa.
New Data from a Large Randomized Trial With Serostatus Defined
Also last week, the large single shot J&J vaccine placebo controlled trial was published, with 39,185 participants and a median of 4 months follow-up. Within that trial there were over 2,000 participants who unknowingly had Prior Covid but tested positive by nucleocapsid antibody, and were assigned to placebo. They were compared with almost 19,000 people who were assigned placebo and were seronegative. The finding: "Previous infection alone, in an analysis involving seropositive and seronegative placebo recipients, was found to provide 90.4% (95% CI, 83.2 to 95.1) protection against moderate to severe–critical Covid-19.” That 90% is substantially more than the overall trial vaccine’s 56% protection (point estimates, Figure below). As far as I know, there is no other large randomized study with systematic serostatus assessment, that is placebo-controlled, with follow-up. For perspective, the United States/CDC still categorizes 1 shot of the J&J vaccine as “fully vaccinated” but Prior Covid, which carries a substantially higher level of protection, is left without any recognition.
Two Reviews With Different Conclusions
A recent Annals Internal Medicine systematic review of Prior Covid and vaccination concluded “Although natural immunity remains a topic of scientific interest…..vaccination is the best clinical recommendation for preventing infection, reinfection, and serious illness from SARS-CoV-2 and its variants.” This was an exhaustive review of hundreds of studies which pointed out that more than 90% of people with Prior Covid develop neutralizing antibodies and that the risk of reinfection is reduced by 84 to 90%. The 18 new studies led these researchers to emphasize the “uncertainty about the level and duration protection that natural immunity confers.”
Another brief review of the literature by Kojima and Klausner in The Lancet Infectious Diseases had a different conclusion; “Given the evidence of immunity from previous SARS-CoV-2 infection, however, policy makers should consider recovery from previous SARS-CoV-2 infection equal to immunity from vaccination for purposes related to entry to public events, businesses, and the workplace, or travel requirements.”
Therein lies much of the data and the crux of the debate. Is Prior Covid as good as vaccination and why are people with confirmed Covid getting mandated to be vaccinated?
The Debate, Intensified
This was further fueled by a recent CDC MMWR on Covid cases and hospitalizations in in New York and California that showed, during the Delta wave, a very low rate of hospitalizations in people who were unvaccinated but had Prior Covid. In this report, in the California cohort, the cumulative incidence of California hospitalizations was 0.7% in the vaccinated group compared with 0.3% unvaccinated group, but the number of people markedly differed: 10,737 vs 378, respectively. In a recent Wall Street Journal editorial, Dr. Marty Makary railed against the vaccine mandates and commented on this report: “the CDC released data from New York and California, which demonstrated natural immunity was 2.8 times as effective in preventing hospitalization and 3.3 to 4.7 times as effective in preventing Covid infection compared with vaccination.” A quick look at the graph below would point out that the math for any difference for hospitalizations is at a very low level for both groups, and, as mentioned, the number of people for such calculus is based on in the Prior Covid group is limited. Nevertheless, the protection from hospitalization among people with Prior Covid cannot be dismissed.
Another study that is frequently cited by proponents of infection-induced immunity is from Israel that “demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 [Pfizer] two-dose vaccine-induced immunity.” What is often omitted, however, is that a single dose of vaccine in this study gave significantly higher protection to people with Prior Covid.
Which brings us to hybrid immunity. The vaccine immunity is specific to the spike protein, whereas the immunity from infection is directed to the whole virus, and it is clear they are complementary. Every study, and there are more than 25, that has looked at neutralizing antibodies and memory B and T cells has showed there is synergy (beyond additivity) of the immune response when a person has both forms of immunity. The Science Magazine succinct review by Shane Crotty is outstanding, with the summary Figure below
The Unnecessary War
This week, Martin Kulldorf, with whom I debated on this and related topics last year, wrote on twitter: “The denial of natural immunity after Covid disease is the worst unscientific folly in the past 75 years.” That is hyperbole, but it is clear there has indeed been denial. For example, beyond the previous data cited, a new study for neutralizing antibody dynamics in people with Prior Covid out to 16 months showed high levels of durable activity. This was also seen for memory B cells after Prior Covid at 15 months. And there is a study of over 7,000 UK health care workers: ”We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years.”
The CDC has been completely unwilling to recognize confirmed Prior Covid as equivalent to at least 1-dose or 2-doses of vaccines. While mandates worked to increase the number of people who got vaccinated in the United States, they have augmented the divisiveness among those with Prior Covid who rightfully believe they have immunity. The studies that I’ve reviewed all have the problem of survivor bias (i.e. people who died with Prior Covid, not studied), and the marked heterogeneity and durability of the immune response for the spectrum of symptoms (from none to severe). And there is the unpredictability of Covid. That vaccination provides some protection versus Long Covid, which is absent from infection. But what I am referring to here is that people who had prior Covid deserve respect for having a level of immunity that is at least comparable to vaccination and would certainly be enhanced with a dose of a vaccine.
Last August, I lobbied the CDC to at least provide equivalency of Prior Covid to 1-dose of vaccine. Their response was “it was too complicated” and that it wouldn’t be pursued. I think that position is indefensible, given the simple requirement for the individual to have proof of a positive PCR test. Not only is there the issue of the waste of vaccines at scale, but the deeper problem of negating a large body of data—the science—which, at the very least, supports the position that infection-induced immunity provides protection.
Then Came Omicron
Things have changed since the Omicron variant, with its extreme of immune evasion, became dominant in many countries throughout the world. Reinfection quickly spiked among people with prior Covid, when previously in the UK it was quite rare, now up to a 16-fold risk. The risk was further substantiated by the report from Qatar in this week’s NEJM that Prior Covid protection vs symptomatic reinfection was high, about 90% for prior variants, but dropped down to 56% with Omicron.
Now it appears Prior Covid induced immunity is not holding up nearly as well as previously, and makes the case for at least 1-shot of a vaccine. What is also happening at scale are Omicron breakthrough infections in people who did not have Prior Covid, but had 2 or 3-shots of vaccines. This other timing of hybrid immunity confers benefit for a greater breadth of neutralizing antibody response. A reductionist way I put it is “Three spikes and you’re out” from a recent Nature Medicine paper that showed, for any combination of 3 exposures to the virus’s spike protein, be it Prior Covid or vaccination, strong immunity is induced vs Omicron. Nevertheless, it should also be noted, from a new large UK report that Prior Covid vs Omicron, without vaccination, was highly protective vs death .
The United States had and still has an opportunity to recognize the value of infection-induced (aka natural) immunity. Many countries throughout the world have done this as part of their vaccination campaigns. That doesn’t mean it advocates anyone purposely getting Covid, which would be reckless, but recognizes there is unequivocal evidence for it providing a path to protection. It is part of the immunity wall, a term I have been using for many months, that has been building in this country, and is still inadequate to protect vs the current version of the virus, no less subsequent variants. Many unvaccinated people with Prior Covid have been lost along the way, and so have people who have been vaccinated but waned, without a booster. It is long overdue that the CDC gives credit to confirmed Prior Covid on “vaccination” cards, which should, of course, be digital and incorporate proof of a positive test (“immunity certificates”) for those with prior infection who wish to avoid multiple vaccines. This saga could have been avoided if there was objective assessment of the many evolving, high-quality datasets and avoidance of vaccination tunnel vision. And willingness to take appropriate and bold action, for which there’s been a dearth throughout the pandemic.