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

BMJ 2021; 374 doi: https://doi.org/ten.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 U.s. CDC estimates that SARS-CoV-2 has infected more than 100 million Americans, and show is mounting that natural immunity is at least every bit 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 one quarter of Americans—91 one thousand thousand—had been infected with SARS-CoV-2, according to a Us Centers for Disease Control and Prevention (CDC) estimate.1 As of this May, that proportion had risen to more than a 3rd of the population, including 44% of adults aged 18-59 (table 1).

Tabular array 1

Estimated total infections in the United States between February 2020 and May 2021*

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

"The CDC could say [to people who had recovered], very well grounded in excellent data, that you lot should wait 8 months," Monica Gandhi, an infectious disease specialist at University of California San Francisco, told Medpage Today in January. She suggested authorities inquire people to "delight await your turn."4

Others, such as Icahn Schoolhouse of Medicine virologist and researcher Florian Krammer, argued for 1 dose in those who had recovered. "This would also spare individuals from unnecessary hurting when getting the second dose and it would gratuitous upwardly additional vaccine doses," he told the New York Times.five

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

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

As more Us employers, local governments, and educational institutions upshot vaccine mandates that brand no exception for those who have had covid-19,8 questions remain nigh the science and ethics of treating this group of people as equally vulnerable to the virus—or as 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 united states that retention B cells and retentivity 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 hand.91011

Gandhi included a listing of some twenty references on natural immunity to covid in a long Twitter thread supporting the durability of both vaccine and infection induced amnesty.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 establish "durable allowed responses" in 95% of the 200 participants upwards to 8 months after infection.13 One of the largest studies to date, published in Scientific discipline in Feb 2021, found that although antibodies declined over 8 months, memory B cells increased over fourth dimension, and the half life of memory CD8⁺ and CD4⁺ T cells suggests a steady presence.nine

Real world data have as well been supportive.14 Several studies (in Qatar,fifteen England,16 Israel,17 and the US18) take found infection rates at as depression levels among people who are fully vaccinated and those who have previously had covid-19. Cleveland Dispensary surveyed its more than 50 000 employees to compare iv groups based on history of SARS-CoV-two infection and vaccination status.eighteen Not one of over 1300 unvaccinated employees who had been previously infected tested positive during the 5 months of the study. Researchers concluded that that cohort "are unlikely to do good from covid-nineteen vaccination." In Israel, researchers accessed a database of the entire population to compare the efficacy of vaccination with previous infection and plant nearly identical numbers. "Our results question the need to vaccinate previously infected individuals," they ended.17

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

But as the delta variant and rising instance counts have the U.s.a. on edge, renewed vaccination incentives and mandates use regardless of infection history.eight To attend Harvard Academy 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'south highest part. In a recent spoken language 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 health necessity or personal benefit of vaccinating people who have had covid-19: "Nosotros accept a pandemic because of the unvaccinated ... Then, get vaccinated. If you haven't, you're non nearly as smart as I said you were."

Staying firm

Other countries do give by infection some immunological currency. Israel recommends that people who accept had covid-19 wait 3 months before getting one mRNA vaccine dose and offers a "light-green pass" (vaccine passport) to those with a positive serological outcome regardless of vaccination.xix In the Eu, people are eligible for an EU digital covid certificate after a single dose of an mRNA vaccine if they have had a positive test outcome within the past half dozen months, allowing travel between 27 EU member states.twenty In the UK, people with a positive polymerase chain reaction (PCR) examination issue can obtain the NHS covid turn down until 180 days after infection.21

Although it's too soon to say whether these systems are working smoothly or mitigating spread, the The states has no category for people who have been infected. The CDC still recommends a full vaccination dose for all, which is at present beingness mirrored in mandates. A spokesperson told The BMJ that "the immune response from vaccination is more than anticipated" and that based on current evidence, antibiotic responses after infection "vary widely by private," 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'due south Center for Biologics Evaluation and Research, which regulates vaccines, went a step further and stated: "We do know that the amnesty after vaccination is better than the amnesty after natural infection." In an email, an FDA spokesperson said Marks's annotate was based on a laboratory written report of the binding breadth of Moderna vaccine induced antibodies.22 The enquiry did not measure out any clinical outcomes. Marks added, referring to antibodies, that "generally the immunity later natural infection tends to wane after well-nigh 90 days."23

"It appears from the literature that natural infection provides amnesty, but that immunity is seemingly not as stiff and may non be as long lasting as that provided past the vaccine," Alfred Sommer, dean emeritus of the Johns Hopkins Bloomberg Schoolhouse of Public Wellness tells The BMJ.

But not everyone agrees with this interpretation. "The data we have right now suggests that at that place 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 every bit the Cleveland Clinic study18 and points out that while "vaccines are focused on merely that tiny portion of amnesty that tin exist induced" by the fasten, someone who has had covid-19 was exposed to the whole virus, "which would likely offer a broader based amnesty" that would be more protective against variants. The laboratory study offered by the FDA22 "just has to do with very specific antibodies to a very specific region of the virus [the fasten]," says Memoli. "Claiming this as information supporting that vaccines are amend than natural immunity is shortsighted and demonstrates a lack of agreement of the complication of immunity to respiratory viruses."

Antibodies

Much of the fence 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 "additional" past vaccination because "your antibodies will go sky loftier."

"That's nonetheless what we're hearing from Dr Fauci—he'south a potent 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 outcome" 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 Nevertheless, Memoli questions the importance: "We don't know that that means it'south ameliorate protection."

Former CDC manager Tom Frieden, a proponent of universal vaccination, echoes that doubtfulness: "We don't know that antibody level is what determines protection."

Gandhi and others take been urging reporters abroad from antibodies as the defining metric of immunity. "Information technology is authentic that your antibodies will go downwards" after natural infection, she says—that'southward how the immune system works. If antibodies didn't clear from our bloodstream after nosotros recover from a respiratory infection, "our blood would be thick every bit molasses."

"The real memory in our immune system resides in the [T and B] cells, non in the antibodies themselves," says Patrick Whelan, a paediatric rheumatologist at University of California, Los Angeles. He points out that his sickest covid-xix patients in intensive intendance, including children with multisystem inflammatory syndrome, take "had loads of antibodies ... So the question is, why didn't they protect them?"

Antonio Bertoletti, a professor of infectious affliction at Duke-NUS Medical School in Singapore, has conducted research that indicates T cells may be more important than antibodies. Comparing the T jail cell response in people with symptomatic versus asymptomatic covid-nineteen, Bertoletti's squad constitute them to exist identical, suggesting that the severity of infection does non predict strength of resulting immunity and that people with asymptomatic infections "mount a highly functional virus specific cellular allowed response."25

Already complicated rollout

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

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

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

Klausner, who is likewise a medical director of a US testing and vaccine distribution company, says he initiated conversations about offering a fingerprick antibody screen for people with suspected exposure earlier vaccination, so that doses could be used more than judiciously. But "everyone concluded it was just too complicated."

"Information technology's a lot easier to put a shot in their arm," says Sommer. "To do a PCR test or to exercise an antibiotic exam and so to process it and and so to get the information to them and so to let them remember virtually it—it'south a lot easier to but requite them the damn vaccine." In public health, "the principal objective is to protect equally many people every bit you tin can," he says. "It's chosen collective insurance, and I think information technology'south irresponsible from a public health perspective to let people pick and choose what they want to do."

But Klausner, Gandhi, and others heighten the question of fairness for the millions of Americans who already have records of positive covid exam results—the footing for "recovered" status in Europe—and disinterestedness for those at risk who are waiting to get their first dose (an statement being raised anew equally US officials denote boosters while the virus spreads in countries lacking vaccine supply). For people who did not have a confirmed positive result merely suspected previous infection, reliable antibiotic tests have been accessible "at least since April," according to Klausner, though in May, the FDA announced that "antibiotic tests should non be used to evaluate a person'south level of amnesty or protection from covid-19 at whatsoever time."26

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

Gandhi thinks logistics is but part of the story. "There'southward a very clear bulletin out there that 'OK, well natural infection does cause immunity only it'due south yet better to get vaccinated,' and that message is not based on information," says Gandhi. "There's something political going on around that."

Politics of natural amnesty

Early in the pandemic, the question of natural immunity was on the mind of Ezekiel Emanuel, a bioethicist at the University of Pennsylvania and senior young man at the liberal recall tank Centre for American Progress, who later became a covid adviser to President Biden. He emailed Fauci before dawn on 4 March 2020. Within a few hours, Fauci wrote back: "yous would assume that their [sic] would be substantial immunity mail infection."27

That was before natural immunity started to exist promoted by Republic politicians. In May 2020, Kentucky senator and medico Rand Paul asserted that since he already had the virus, he didn't demand to vesture a mask. He has been the most vocal since, arguing that his immunity exempted him from vaccination. Wisconsin senator Ron Johnson and Kentucky representative Thomas Massie have too spoken out. And and then at that place was President Trump, who tweeted last October that his recovery from covid-19 rendered him "immune" (which Twitter labelled "misleading and potentially harmful data").

Another polarising gene may have been the Nifty Barrington declaration of October 2020, which argued for a less restrictive pandemic strategy that would help build herd immunity through natural infections in people at minimal take chances.28 The John Snow memorandum, written in response (with signatories including Rochelle Walensky, who went on to head the CDC), stated "in that location is no evidence for lasting protective immunity to SARS-CoV-2 following natural infection."29 That statement has a footnote to a study 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 study aiming to characterise the protection a vaccine might give to people with past infections. Comparison 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.xxx The report notes the limitation that the vaccinated are "peradventure less likely to get tested. Therefore, the association of reinfection and lack of vaccination might be overestimated." In announcing the study, Walensky stated: "If yous accept had covid-19 before, please still become vaccinated."31

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

Unlike risk-benefit analysis?

For Frieden, vaccinating people who have already had covid-19 is, ultimately, the nigh responsible policy correct at present. "There'southward no doubt that natural infection does provide significant immunity for many people, but we're operating in an environment of imperfect data, and in that surround the precautionary principle applies—better safety than distressing."

"In public health you are ever dealing with some level of unknown," says Sommer. "But the bottom line is you want to salve lives, and you have to practise what the present prove, as weak every bit it is, suggests is the strongest defense with the least corporeality of harm."

Only others are less certain.

"If natural amnesty is strongly protective, as the evidence to date suggests it is, so vaccinating people who have had covid-19 would seem to offer nothing or very petty to benefit, logically leaving only harms—both the harms nosotros already know about likewise as those nonetheless unknown," says Christine Stabell Benn, vaccinologist and professor in global health at the Academy of Southern Denmark. The CDC has best-selling the small-scale merely serious risks of heart inflammation and blood clots after vaccination, especially in younger people. The real risk in vaccinating people who have had covid-nineteen "is of doing more damage than skilful," she says.

A big study in the UK32 and another that surveyed people internationally33 found that people with a history of SARS-CoV-2 infection experienced greater rates of side effects after vaccination. Among 2000 people who completed an online survey afterwards vaccination, those with a history of covid-19 were 56% more probable to feel a severe side event that required infirmary care.33

Patrick Whelan, of UCLA, says the "sky high" antibodies subsequently vaccination in people who were previously infected may have contributed to these systemic side effects. "Most people who were previously ill with covid-nineteen have antibodies against the fasten protein. If they are afterward vaccinated, those antibodies and the products of the vaccine can form what are chosen immune complexes," he explains, which may get deposited in places similar the joints, meninges, and fifty-fifty kidneys, creating symptoms.

Other studies suggest that a two dose regimen may exist counterproductive.34 Ane found that in people with by infections, the first dose boosted T cells and antibodies but that the second dose seemed to indicate an "exhaustion," and in some cases even a deletion, of T cells.34 "I'k not here to say that it'south harmful," says Bertoletti, who coauthored the study, "but at the moment all the data are telling us that it doesn't brand whatsoever sense to give a 2d vaccination dose in the very curt term to someone who was already infected. Their immune response is already very loftier."

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

"When the vaccine was rolled out the goal should accept been to focus on people at risk, and that should still exist the focus," says Memoli. Such risk stratification may have complicated logistics, but it would besides require more than nuanced messaging. "A lot of public health people have this notion that if the public is told that there'due south even the slightest bit of uncertainty well-nigh a vaccine, then they won't become it," he says. For Memoli, this reflects a foretime paternalism. "I always think it's much amend to be very articulate and honest about what we 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 accept no relevant interests to declare.

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

This article is made freely available for use in accordance with BMJ'south website terms and weather condition for the duration of the covid-19 pandemic or until otherwise determined by BMJ. Yous may use, download and impress the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

https://bmj.com/coronavirus/usage

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

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