Virus World

The term ‘fully vaccinated’ needs to be redefined. It’s time for the United States and the CDC to see natural immunity as a partial path to protection. The US Centers for Disease Control and Prevention (CDC) has failed to recognize that people with confirmed Covid infections, also known as “natural immunity,” have achieved some level of protection against subsequent infections and severe disease. This has unnecessarily fueled divisiveness, particularly when vaccines are mandated without acknowledgement that prior Covid is an alternate path, albeit with some limitations, for protection of the individual and helping to build the population’s immunity wall. While there has been a body of data supporting a robust immune response to Covid infections, that evidence has recently been substantially bolstered. In the very large trial on the Johnson and Johnson vaccine single shot compared with placebo, among over 2,000 participants with prior infections, as documented by positive antibody status, their protection against moderate or severe disease was 90%. That’s much higher than the vaccine efficacy of 56%, yet the CDC recognizes 2-shot of this vaccine as “fully vaccinated” but ignores these data, and many other proof points, of natural immunity protection.

A recent CDC report for Covid in California that included the Delta wave, the cumulative hospitalization rate for the vaccinated was 0.7% among vaccinated and 0.3% unvaccinated with prior infection. Notably, a 10-fold lower risk of subsequent infection was found in the people with natural immunity compared with those vaccinated in the Cleveland Clinic health system’s study of over 52,000 employees. These reports convey a high level of protection of natural immunity, at times comparable to 2-shot vaccines. Multiple studies following people at least 15 months out from Covid infections have shown persistent antibody levels and memory B cells. Reinfections among those with natural immunity throughout the pandemic, until the recent Omicron wave, have been very low, less than 1%. A United Kingdom study of about 9,000 people with prior infections demonstrated higher than 90% protection against subsequent infections, even among those who had Covid more than 18 months previously. If there is good protection from infections, then why is one-shot of a vaccine necessary and sufficient? A new report of nearly 150,000 people with Covid infections in Israel, with about half vaccinated, compared to the others left unvaccinated, there was an 82% lower risk of reinfection for people aged 16 to 64 years, and 60% for age 65 or older. There was no difference for the protection with more than 1-dose of vaccine. The same was found in another study. Both of these were performed during the Delta wave, but now we have data with Omicron, the strain of the virus with the most substantial evasion of our immune system. Substantiating that, In Qatar, while the protection of natural immunity was about 90% for previous Alpha, Beta and Gamma variants, it dropped to 56% for Omicron. In the United Kingdom, the risk of reinfection for people with prior Covid spiked to a level 16-fold what had been seen previously. Yet an Omicron wave study from Cleveland Clinic in about 8,000 people with natural immunity, 1-shot of vaccine markedly reduced the risk of infection and 2 or 3-shots had no incremental protective benefit. That same finding was consistent in the Israel and UK studies: 1-shot did the trick, no added protection from 2 or 3-shots. Indeed, the waning of protection after 1-year in the UK study was averted with one dose of vaccine.

Past critique of natural immunity protection is still relevant. These studies have survivor bias—they only include people who survived their infections. We know that the symptoms of Long Covid can be reduced by vaccines, which is an important added feature of the controlled vaccine approach compared with the unpredictable chronic duration sequalae of an infection, which can be disabling, even when they are mild. Although about 90% of people with infections develop antibodies and memory B an T cells, that leaves some without an immune response, which appears to be more of an issue when a person did not have symptoms, or they were very mild. Since we do not assess antibody levels, especially those capable of neutralizing of the virus, and do not measure T cell responses, there is a blind spot in knowing about an individual’s level of protection, be it by infection or vaccination. Which brings us to hybrid immunity. It would be reckless to ever recommend someone get purposely infected with Covid. However, for those who have sustained an infection their immune response was directed to the whole virus whereas our vaccines are specific to the spike-protein. The result of combining the different immune responses is synergy, more than additive, a powerful and durable protection, 25 to 100 times more antibody response and broader against variants of the virus. Note that we do not have the same evidence for the opposite order: vaccination prior to breakthrough infections.

It is now clearly overdue for the United States and the CDC to acknowledge natural immunity as a partial path to protection, as has been previously done in several countries. The term “fully vaccinated” needs to be redefined. For people who have received 2 mRNA vaccine shots, without prior infection, a third shot, booster, is needed to protect against symptomatic and severe disease. On the other hand, for people with natural immunity, with proof of a positive PCR test, one-shot is all that is necessary to be considered “fully vaccinated.” By providing immunity certification in this way, the polarization between natural and vaccine-induce immune camps will be bridged, at least to some extent. The evidence has become overwhelming and its adoption as policy will likely help get the low American vaccination rate of 64% , ranked worse than 60 countries in the world, to a much higher level, further building the immunity wall for the whole population. It’s also about sticking to the science when a large and ever-increasing body of data can no longer be ignored. One can fully understand why vaccine mandates would be repudiated when there was evidence of protection conferred by infection. Now, as the virus evolved, we are at a time when natural immunity alone is not sufficient, but with a single shot it’s as good as three.

• Eric Topol is the founder and director of the Scripps Research Translational Institute, professor of molecular medicine, and executive vice-president of Scripps Research

Background: Following a single dose of BNT162b2 mRNA vaccine, higher antibody titres are observed following prior SARS-CoV-2 infection than in infection-naive individuals, but T-cell responses are less well defined.

Methods: We sampled healthcare workers (HCWs) enrolled in the UK PITCH study, before and after BNT162b2 mRNA vaccination. We measured spike-specific antibody, and quantified T-cell responses by IFNγ ELISpot assay and intracellular staining of peripheral blood mononuclear cells (PBMC), comparing SARS-CoV-2-naïve individuals to those with prior infection.

Findings: HCWs aged 22 to 71 years received one (n=216) or two (n=21) vaccine doses. After a single dose, the spike-specific T-cell response was six-fold higher in previously-infected vs. naive individuals (median 340 vs. 58 SFU/106 PBMC, p<0.0001; fresh PBMC, n=99). The T-cell response in previously-infected individuals after one vaccine dose was equivalent to naïve individuals receiving two vaccine doses (median 158 vs. 165 SFU/106 PBMCs, p=0.65; cryopreserved PBMC, n=117). Anti-spike IgG levels following a single dose in those previously infected (median 512.9 antibody units/ml (AU/ml)) were 6.8-fold higher vs. naïve individuals following one dose (median 75.0 AU/ml, p<0.0001) and 2.9-fold higher than naïve individuals given two doses three weeks apart (179.9 AU/ml, p=0.03). Following vaccination, plasma from individuals with prior infection demonstrated higher in vitro neutralisation of the B.1.351 variant of concern compared to naive individuals.

Interpretation: Following a single BNT162b2 dose, HCWs with a prior history of SARS-CoV-2 infection have significantly higher T-cell and antibody responses than naive individuals.Funding UK Department of Health and Social Care and UK Coronavirus Immunology Consortium.

Available as preprint in The Lancet (March 25, 2021):

http://dx.doi.org/10.2139/ssrn.3812375 

Background

Methods

Findings

Interpretation

SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.

Published in Science (April 30, 2021):

https://doi.org/10.1126/science.abh1282