Other countries do give past infection some immunological currency. Israel recommends that people who have had covid-19 wait three months before getting one mRNA vaccine dose and offers a “green pass” (vaccine passport) to those with a positive serological result regardless of vaccination.19 In the European Union, people are eligible for an EU digital covid certificate after a single dose of an mRNA vaccine if they have had a positive test result within the past six months, allowing travel between 27 EU member states.20 In the UK, people with a positive polymerase chain reaction (PCR) test result can obtain the NHS covid pass up until 180 days after infection.21
Although it’s too soon to say whether these systems are working smoothly or mitigating spread, the US has no category for people who have been infected. The CDC still recommends a full vaccination dose for all, which is now being mirrored in mandates. A spokesperson told The BMJ that “the immune response from vaccination is more predictable” and that based on current evidence, antibody responses after infection “vary widely by individual,” though studies are ongoing to “learn how much protection antibodies from infection may provide and how long that protection lasts.”
In June, Peter Marks, director of the Food and Drug Administration’s Center for Biologics Evaluation and Research, which regulates vaccines, went a step further and stated: “We do know that the immunity after vaccination is better than the immunity after natural infection.” In an email, an FDA spokesperson said Marks’s comment was based on a laboratory study of the binding breadth of Moderna vaccine induced antibodies.22 The research did not measure any clinical outcomes. Marks added, referring to antibodies, that “generally the immunity after natural infection tends to wane after about 90 days.”23
“It appears from the literature that natural infection provides immunity, but that immunity is seemingly not as strong and may not be as long lasting as that provided by the vaccine,” Alfred Sommer, dean emeritus of the Johns Hopkins Bloomberg School of Public Health tells The BMJ.
But not everyone agrees with this interpretation. “The data we have right now suggests that there probably isn’t a whole lot of difference” in terms of immunity to the spike protein, says Matthew Memoli, director of the Laboratory of Infectious Diseases Clinical Studies at the NIH, who spoke to The BMJ in a personal capacity.
Memoli highlights real world data such as the Cleveland Clinic study18 and points out that while “vaccines are focused on only that tiny portion of immunity that can be induced” by the spike, someone who has had covid-19 was exposed to the whole virus, “which would likely offer a broader based immunity” that would be more protective against variants. The laboratory study offered by the FDA22 “only has to do with very specific antibodies to a very specific region of the virus [the spike],” says Memoli. “Claiming this as data supporting that vaccines are better than natural immunity is shortsighted and demonstrates a lack of understanding of the complexity of immunity to respiratory viruses.”
Antibodies
Much of the debate pivots on the importance of sustained antibody protection. In April, Anthony Fauci told US radio host Maria Hinajosa that people who have had covid-19 (including Hinajosa) still need to be “boosted” by vaccination because “your antibodies will go sky high.”
“That’s still what we’re hearing from Dr Fauci—he’s a strong believer that higher antibody titres are going to be more protective against the variants,” says Jeffrey Klausner, a clinical professor of preventive medicine at the University of Southern California and former CDC medical officer, who has spoken out in favour of treating prior infection as equivalent to vaccination, with “the same societal status.”3 Klausner conducted a systematic review of 10 studies on reinfection and concluded that the “protective effect” of a previous infection “is high and similar to the protective effect of vaccination.”
In vaccine trials, antibodies are higher in participants who were seropositive at baseline than in those who were seronegative.24 However, Memoli questions the importance: “We don’t know that that means it’s better protection.”
Former CDC director Tom Frieden, a proponent of universal vaccination, echoes that uncertainty: “We don’t know that antibody level is what determines protection.”
Gandhi and others have been urging reporters away from antibodies as the defining metric of immunity. “It is accurate that your antibodies will go down” after natural infection, she says—that’s how the immune system works. If antibodies didn’t clear from our bloodstream after we recover from a respiratory infection, “our blood would be thick as molasses.”
“The real memory in our immune system resides in the [T and B] cells, not in the antibodies themselves,” says Patrick Whelan, a paediatric rheumatologist at University of California, Los Angeles. He points out that his sickest covid-19 patients in intensive care, including children with multisystem inflammatory syndrome, have “had loads of antibodies ... So the question is, why didn’t they protect them?”
Antonio Bertoletti, a professor of infectious disease at Duke-NUS Medical School in Singapore, has conducted research that indicates T cells may be more important than antibodies. Comparing the T cell response in people with symptomatic versus asymptomatic covid-19, Bertoletti’s team found them to be identical, suggesting that the severity of infection does not predict strength of resulting immunity and that people with asymptomatic infections “mount a highly functional virus specific cellular immune response.”25
