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Vaccinating people who have had covid-19: why doesn't natural immunity count in the U.s.a.?

BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n2101 (Published 13 September 2021) Cite this as: BMJ 2021;374:n2101

Read our latest coverage of the coronavirus pandemic

1. Jennifer Block , freelance announcer

1. New York, USA

1. writingblock{at}protonmail.com
   Twitter: @writingblock

The US CDC estimates that SARS-CoV-2 has infected more than 100 one thousand thousand Americans, and evidence is mounting that natural immunity is at to the lowest degree as protective as vaccination. Yet public health leadership says everyone needs the vaccine. Jennifer Block investigates

When the vaccine rollout began in mid-December 2020, more than i quarter of Americans—91 million—had been infected with SARS-CoV-2, co-ordinate to a United states of america Centers for Disease Command and Prevention (CDC) estimate.1 As of this May, that proportion had risen to more than a third of the population, including 44% of adults aged 18-59 (tabular array one).

Table 1

Estimated total infections in the United states between Feb 2020 and May 2021*

The substantial number of infections, coupled with the increasing scientific evidence that natural immunity was durable, led some medical observers to ask why natural immunity didn't seem to be factored into decisions nigh prioritising vaccination.234

"The CDC could say [to people who had recovered], very well grounded in fantabulous data, that you should expect 8 months," Monica Gandhi, an infectious disease specialist at University of California San Francisco, told Medpage Today in January. She suggested government enquire people to "please look your plow."4

Others, such as Icahn School of Medicine virologist and researcher Florian Krammer, argued for ane dose in those who had recovered. "This would also spare individuals from unnecessary hurting when getting the second dose and information technology would gratis upward boosted vaccine doses," he told the New York Times.five

"Many of us were saying let's use [the vaccine] to save lives, not to vaccinate people already immune," says Marty Makary, a professor of health policy and management at Johns Hopkins Academy.

Still, the CDC instructed everyone, regardless of previous infection, to get fully vaccinated as soon as they were eligible: natural immunity "varies from person to person" and "experts do not yet know how long someone is protected," the agency stated on its website in Jan.6 By June, a Kaiser Family unit Foundation survey found that 57% of those previously infected got vaccinated.7

As more US employers, local governments, and educational institutions issue vaccine mandates that make no exception for those who accept had covid-19,8 questions remain nigh the science and ethics of treating this group of people as as vulnerable to the virus—or equally equally threatening to those vulnerable to covid-19—and to what extent politics has played a role.

The evidence

"Starting from back in November, we've had a lot of really important studies that showed us that retention B cells and memory T cells were forming in response to natural infection," says Gandhi. Studies are also showing, she says, that these memory cells will respond by producing antibodies to the variants at paw.91011

Gandhi included a list of some 20 references on natural amnesty to covid in a long Twitter thread supporting the immovability of both vaccine and infection induced immunity.12 "I stopped adding papers to information technology in Dec because it was getting so long," she tells The BMJ.

But the studies kept coming. A National Institutes of Health (NIH) funded study from La Jolla Institute for Immunology institute "durable immune responses" in 95% of the 200 participants upwards to eight months after infection.13 I of the largest studies to date, published in Scientific discipline in February 2021, found that although antibodies declined over 8 months, retention B cells increased over fourth dimension, and the half life of retentiveness CD8⁺ and CD4⁺ T cells suggests a steady presence.nine

Existent world data have also been supportive.14 Several studies (in Qatar,15 England,16 Israel,17 and the US18) have found infection rates at equally low levels amidst people who are fully vaccinated and those who have previously had covid-xix. Cleveland Dispensary surveyed its more than 50 000 employees to compare four groups based on history of SARS-CoV-ii infection and vaccination condition.18 Non one of over 1300 unvaccinated employees who had been previously infected tested positive during the five months of the study. Researchers concluded that that cohort "are unlikely to benefit from covid-19 vaccination." In Israel, researchers accessed a database of the entire population to compare the efficacy of vaccination with previous infection and institute nigh identical numbers. "Our results question the need to vaccinate previously infected individuals," they concluded.17

As covid cases surged in Israel this summer, the Ministry of Health reported the numbers past immunity status. Between 5 July and three August, just ane% of weekly new cases were in people who had previously had covid-19. Given that 6% of the population are previously infected and unvaccinated, "these numbers look very depression," says Dvir Aran, a biomedical information scientist at the Technion–Israel Found of Technology, who has been analysing Israeli data on vaccine effectiveness and provided weekly ministry building reports to The BMJ. While Aran is cautious about drawing definitive conclusions, he acknowledged "the information suggest that the recovered have better protection than people who were vaccinated."

Merely as the delta variant and ascent example counts accept the US on edge, renewed vaccination incentives and mandates utilize regardless of infection history.8 To attend Harvard University or a Foo Fighters concert or enter indoor venues in San Francisco and New York City, you need proof of vaccination. The ire being directed at people who are unvaccinated is also indiscriminate—and emanating from America'southward highest office. In a recent speech communication to federal intelligence employees who, along with all federal workers, will be required to get vaccinated or submit to regular testing, President Biden left no room for those questioning the public wellness necessity or personal do good of vaccinating people who have had covid-xix: "Nosotros have a pandemic because of the unvaccinated ... So, get vaccinated. If you haven't, you're not virtually as smart as I said y'all were."

Staying firm

Other countries exercise give by infection some immunological currency. Israel recommends that people who have had covid-xix wait 3 months before getting one mRNA vaccine dose and offers a "green pass" (vaccine passport) to those with a positive serological event 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 take had a positive exam result within the past six months, allowing travel between 27 European union member states.xx In the UK, people with a positive polymerase chain reaction (PCR) test event 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 U.s.a. has no category for people who have been infected. The CDC withal recommends a total vaccination dose for all, which is at present being mirrored in mandates. A spokesperson told The BMJ that "the immune response from vaccination is more predictable" and that based on current bear witness, antibiotic responses subsequently 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, manager of the Nutrient and Drug Administration'south Center for Biologics Evaluation and Enquiry, which regulates vaccines, went a step further and stated: "We do know that the amnesty afterwards vaccination is meliorate than the immunity after natural infection." In an email, an FDA spokesperson said Marks'southward comment was based on a laboratory study of the binding breadth of Moderna vaccine induced antibodies.22 The research did non mensurate whatsoever 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 amnesty, simply that immunity is seemingly not every bit strong and may not be as long lasting as that provided past the vaccine," Alfred Sommer, dean emeritus of the Johns Hopkins Bloomberg Schoolhouse of Public Health tells The BMJ.

Simply non everyone agrees with this estimation. "The information we have correct at present suggests that there probably isn't a whole lot of difference" in terms of amnesty to the fasten poly peptide, 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 Dispensary study18 and points out that while "vaccines are focused on only that tiny portion of immunity that can be induced" by the fasten, someone who has had covid-nineteen was exposed to the whole virus, "which would probable offer a broader based amnesty" that would be more protective against variants. The laboratory report offered past 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 antibiotic protection. In Apr, Anthony Fauci told US radio host Maria Hinajosa that people who have had covid-19 (including Hinajosa) all the same need to be "boosted" by vaccination because "your antibodies will go heaven loftier."

"That's still what we're hearing from Dr Fauci—he's a strong laic that higher antibody titres are going to be more than protective confronting 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 ended that the "protective upshot" of a previous infection "is loftier 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: "Nosotros don't know that that ways it'southward better protection."

Former CDC director Tom Frieden, a proponent of universal vaccination, echoes that dubiousness: "Nosotros 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 authentic that your antibodies volition become down" after natural infection, she says—that's how the immune system works. If antibodies didn't clear from our bloodstream afterward we recover from a respiratory infection, "our blood would exist thick every bit molasses."

"The real memory in our immune arrangement resides in the [T and B] cells, not in the antibodies themselves," says Patrick Whelan, a paediatric rheumatologist at Academy 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 ... And 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 than important than antibodies. Comparing the T cell response in people with symptomatic versus asymptomatic covid-xix, Bertoletti'southward team found them to exist 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

Already complicated rollout

While some debate that the pandemic strategy should not be "1 size fits all," and that natural immunity should count, other public health experts say universal vaccination is a more than quantifiable, predictable, reliable, and feasible style to protect the population.

Frieden told The BMJ that the question of leveraging natural immunity is a "reasonable discussion," i he had raised informally with the CDC at beginning of rollout. "I thought from a rational standpoint, with limited vaccine available, why don't you accept the option" for people with previous infection to defer until there was more supply, he says. "I remember that would have been a rational policy. Information technology would have also fabricated rollout, which was already too complicated, even more complicated."

Near infections were never diagnosed, Frieden points out, and many people may take causeless they had been infected when they hadn't. Add to that false positive results, he says. Had the CDC given different directives and vaccine schedules based on prior infection, it "wouldn't have done much good and might accept done some harm."

Klausner, who is as well a medical director of a US testing and vaccine distribution company, says he initiated conversations about offer a fingerprick antibody screen for people with suspected exposure before vaccination, so that doses could exist used more judiciously. But "anybody ended information technology was simply also complicated."

"Information technology's a lot easier to put a shot in their arm," says Sommer. "To exercise a PCR test or to exercise an antibiotic test and then to process information technology and then to get the information to them and and so to let them think about it—it's a lot easier to just requite them the damn vaccine." In public health, "the master objective is to protect equally many people as you can," he says. "It's called collective insurance, and I remember it's irresponsible from a public wellness perspective to allow people choice and choose what they want to do."

Merely Klausner, Gandhi, and others raise the question of fairness for the millions of Americans who already have records of positive covid test results—the ground for "recovered" status in Europe—and equity for those at run a risk who are waiting to become their first dose (an argument being raised afresh every bit Us officials announce boosters while the virus spreads in countries lacking vaccine supply). For people who did not accept a confirmed positive result but suspected previous infection, reliable antibody tests take been accessible "at least since Apr," according to Klausner, though in May, the FDA appear that "antibody tests should not be used to evaluate a person's level of immunity or protection from covid-19 at whatever time."26

Unlike Europe, the US doesn't have a national certificate or vaccination requirement, and then defenders of natural immunity take simply advocated for more targeted recommendations and screening availability—and that mandates let for exemptions. Logistics bated, a recognition of existing amnesty would have fundamentally changed the target vaccination calculations and would also affect the calculations on boosters. "As we continued to put attempt into vaccination and fix targets, information technology became apparent to me that people were forgetting that herd amnesty is formed by both natural amnesty and vaccine immunity," says Klausner.

Gandhi thinks logistics is only part of the story. "In that location's a very articulate message out there that 'OK, well natural infection does cause immunity but information technology's still better to get vaccinated,' and that message is not based on information," says Gandhi. "At that place's something political going on effectually that."

Politics of natural immunity

Early in the pandemic, the question of natural immunity was on the mind of Ezekiel Emanuel, a bioethicist at the Academy of Pennsylvania and senior boyfriend at the liberal think tank Center for American Progress, who after became a covid adviser to President Biden. He emailed Fauci earlier dawn on 4 March 2020. Within a few hours, Fauci wrote back: "you would assume that their [sic] would be substantial immunity post infection."27

That was before natural immunity started to be promoted by Democracy politicians. In May 2020, Kentucky senator and physician Rand Paul asserted that since he already had the virus, he didn't demand to wear a mask. He has been the most vocal since, arguing that his amnesty exempted him from vaccination. Wisconsin senator Ron Johnson and Kentucky representative Thomas Massie have also spoken out. And and then in that location was President Trump, who tweeted concluding October that his recovery from covid-nineteen rendered him "allowed" (which Twitter labelled "misleading and potentially harmful information").

Another polarising factor may accept been the Nifty Barrington proclamation of October 2020, which argued for a less restrictive pandemic strategy that would help build herd immunity through natural infections in people at minimal risk.28 The John Snowfall memorandum, written in response (with signatories including Rochelle Walensky, who went on to caput the CDC), stated "there is no bear witness for lasting protective immunity to SARS-CoV-2 following natural infection."29 That argument has a footnote to a report of people who had recovered from covid-19, showing that blood antibody levels wane over time.

More recently, the CDC made headlines with an observational written report aiming to characterise the protection a vaccine might give to people with past infections. Comparing 246 Kentuckians who had subsequent reinfections with 492 controls who had non, the CDC concluded that those who were unvaccinated had more than twice the odds of reinfection.30 The written report notes the limitation that the vaccinated are "perhaps less likely to get tested. Therefore, the association of reinfection and lack of vaccination might be overestimated." In announcing the study, Walensky stated: "If you have had covid-19 before, delight still get vaccinated."31

"If yous listen to the linguistic communication of our public health officials, they talk about the vaccinated and the unvaccinated," Makary tells The BMJ. "If we want to exist scientific, we should talk about the immune and the non-allowed." There's a significant portion of the population, Makary says, who are saying, "'Hey, await, I've had [covid].' And they've been blown off and dismissed."

Different chance-benefit analysis?

For Frieden, vaccinating people who take already had covid-xix is, ultimately, the most responsible policy right now. "There'due south no doubt that natural infection does provide meaning immunity for many people, but nosotros're operating in an environment of imperfect data, and in that environment the precautionary principle applies—better safe than sorry."

"In public health you are always dealing with some level of unknown," says Sommer. "But the lesser line is yous want to salve lives, and you take to practise what the present show, as weak as it is, suggests is the strongest defence with the least corporeality of harm."

Simply others are less certain.

"If natural amnesty is strongly protective, as the evidence to date suggests it is, then vaccinating people who have had covid-19 would seem to offer nothing or very little to benefit, logically leaving only harms—both the harms we already know almost every bit well as those still unknown," says Christine Stabell Benn, vaccinologist and professor in global health at the University of Southern Denmark. The CDC has acknowledged the minor only serious risks of heart inflammation and blood clots after vaccination, peculiarly in younger people. The real risk in vaccinating people who take had covid-19 "is of doing more harm than good," she says.

A big written report in the UK32 and another that surveyed people internationally33 plant that people with a history of SARS-CoV-two infection experienced greater rates of side effects afterwards vaccination. Among 2000 people who completed an online survey after vaccination, those with a history of covid-19 were 56% more likely to experience a severe side effect that required hospital care.33

Patrick Whelan, of UCLA, says the "sky high" antibodies after vaccination in people who were previously infected may accept contributed to these systemic side effects. "Near people who were previously ill with covid-19 have antibodies confronting the spike poly peptide. If they are subsequently vaccinated, those antibodies and the products of the vaccine tin course what are called allowed complexes," he explains, which may get deposited in places like the joints, meninges, and even kidneys, creating symptoms.

Other studies suggest that a two dose regimen may be counterproductive.34 1 plant that in people with past infections, the beginning dose additional T cells and antibodies merely that the 2d dose seemed to indicate an "burnout," and in some cases fifty-fifty a deletion, of T cells.34 "I'k not here to say that it'due south harmful," says Bertoletti, who coauthored the study, "but at the moment all the information are telling us that it doesn't make any sense to give a second vaccination dose in the very brusque term to someone who was already infected. Their immune response is already very high."

Despite the extensive global spread of the virus, the previously infected population "hasn't been studied well equally a group," says Whelan. Memoli says he is as well unaware of whatever studies examining the specific risks of vaccination for that grouping. Nevertheless, the US public health messaging has been firm and consistent: anybody should get a full vaccine dose.

"When the vaccine was rolled out the goal should have been to focus on people at risk, and that should still be the focus," says Memoli. Such run a risk stratification may accept complicated logistics, but it would also require more nuanced messaging. "A lot of public health people take this notion that if the public is told that in that location's even the slightest bit of uncertainty near a vaccine, so they won't get it," he says. For Memoli, this reflects a bygone paternalism. "I always think it's much better to be very clear and honest about what nosotros do and don't know, what the risks and benefits are, and allow people to make decisions for themselves."

Footnotes

• Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

• Provenance and peer review: Commissioned; externally peer reviewed.

This commodity is fabricated freely available for use in accordance with BMJ's website terms and atmospheric condition for the duration of the covid-nineteen pandemic or until otherwise determined by BMJ. Y'all may employ, download and impress the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and merchandise marks are retained.

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Source: https://www.bmj.com/content/374/bmj.n2101

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