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  • Researchers of an unpublished study have claimed that one-fifth of people who have had COVID-19 do not have a specific type of antibodies and therefore may not have adequate protection against future infections.
  • The study tested volunteers with a previous SARS-CoV-2 infection for the presence of a type of antibody that only a natural infection can generate called core anti-N antibodies.
  • Smokers and individuals with existing medical conditions were particularly likely to test negative for the antibodies.
  • Critics of the study say the presence of this type of antibody is a poor indicator of overall immunity to future COVID-19 infection.
  • They also point out that surveys relying on the core anti-N antibody may underestimate levels of infection with COVID-19 in the community.

People who have had COVID-19 sometimes argue that they do not need to be vaccinated because their infection has given them immunity against the virus.

But a new study suggests that around a fifth of individuals who recover from COVID-19 may not have adequate protection against future infections.

“Our data shows that the best way to protect yourself and others from COVID-19, even if you have had the virus previously, is to have two doses of vaccine and the booster when offered,” says the study’s lead scientist Dr. Tim Spector, professor of genetic epidemiology at King’s College London in the United Kingdom.

The study found that 19% of people with a previously confirmed infection did not produce anti-N antibodies.

These antibodies target a protein, called the nucleocapsid, found inside SARS-CoV-2, the virus that causes COVID-19.

Only a natural SARS-CoV-2 infection can generate anti-N antibodies, aromatase inhibitor tamoxifen whereas vaccines provoke the production of antibodies against its spike protein, which resides on the outside of the virus.

The study reported on 8,193 adults who reported a previous SARS-CoV-2 infection — confirmed with a PCR test — using the ZOE COVID smartphone app. Each participant also reported at least one symptom in the subsequent 2 weeks and responded to an invitation to undergo home anti-N antibody testing.

The researchers did not provide information on the response rate to their request for additional testing.

The scientists behind the app sent out invites between April 2021 and August 2021. They did not provide information about when the participants logged their positive PCR results.

Overall, 81% of participants tested positive for anti-N antibodies, while 19% tested negative.

Participants who tested negative were more likely to be smokers and have one or more additional medical conditions, or comorbidities.

Conversely, those who tested positive tended to have had more symptoms, or at least one of the classic COVID-19 symptoms of fever, persistent cough, and anosmia — a loss of taste and smell.

Among the participants who tested positive, there was no evidence of a decline in anti-N antibodies for up to 9 months after infection. Therefore, it appears that some participants logged their positive test as early as January or February 2021, but no information was given in the press release and blog about this study.

Dr. Claire Steves, a scientist involved in the ZOE COVID trials and a senior clinical lecturer at King’s College London, says the research indicates that not everyone who has had COVID-19 sustains their antibody response to the virus.

“This underlines the importance of getting vaccinated even if you have had exposure to the virus,” says Dr. Steves.

“Our data show that this is particularly important for people with other preexisting health conditions and people who smoke,” she adds.

Weaknesses of the study

Scientists who spoke to the Science Media Centre in London highlighted several shortcomings of the study, which has not been published either as a preprint or peer-reviewed paper.

“These results are rather simplistic and incomplete,” said Dr. Julian Tang, professor of respiratory sciences at the University of Leicester in the U.K.

He pointed out that the study did not measure the responses of participants’ T cells, which play a vital role in the body’s adaptive immune system alongside B cells, which produce antibodies.

“T cell responses have been investigated previously and can offer immune protection even in the absence of an antibody (B cell) response — or symptomatic infection,” he said.

In addition, he said the study did not measure a class of antibodies known as IgA within mucous membranes. These are a first line of defense against infection in the respiratory tract.

Dr. Tang also cited a study, which found that individuals vary widely in the timing of their antibody responses (IgA and IgG to spike protein) to infection with SARS-CoV-2 from 0–33 days from onset of symptoms.

While not specifically a study relating to anti-N antibody levels, it is possible that the timing of the sample may have affected the findings of the ZOE study. They only tested a single sample from each participant over a period of at least 9 months from symptom onset.

Finally, he pointed out that the ZOE study did not test for the presence of antibodies against other proteins in the virus.

“This is why natural infection with viruses generally provides longer lasting and broader immune protection — compared to vaccination,” said Dr. Tang.

“Vaccination after natural infection boosts the immunity to that particular vaccine target — but that background, primed level of immunity is still protective to some degree — probably for life — as we have previously seen with influenza,” he added.

Core protein

Dr. Simon Clarke, associate professor in cellular microbiology at the University of Reading in the U.K., agreed that testing only for anti-N antibodies was a major limitation of the ZOE study.

“It remains possible that people had antibodies reactive to other coronavirus proteins, which conferred some protection against infection or disease, and this is an obvious research question to ask,” he said.

Dr. Clarke pointed out that the nucleocapsid protein resides in the core of the virus, unlike surface proteins, such as the spike protein, which the virus uses to infect cells.

“Therefore, it’s difficult to envisage exactly how antibodies reactive to N-protein would work to block the virus interacting with our cells or to tag it for destruction by our white blood cells,” he said.

“It might be the case that someone with low anti-N-protein antibodies has a stonking amount of anti-spike protein antibodies and some killer T cells, which confers strong protection,” he added.

Are antibodies essential?

“The fact that people do not necessarily generate antibodies following [SARS-CoV-2] infection or indeed following vaccination is well known,” said Dr. Paul Hunter, professor in medicine at the University of East Anglia in the U.K.

He argued that antibodies are not essential for recovery from COVID-19.

He cited a study, which found that even people with a weakened immune system — making it difficult for them to produce antibodies — may experience only mild COVID-19.

“Although people with lower anti-spike antibody levels tend to be more at risk of reinfection, there is still some degree of protection after infection even with no antibody response,” he said.

It is difficult to interpret this study in relation to a future risk of infection after natural infection, as there is insufficient detail in the press release and blog to determine levels of bias and the effect of other forms of immunity. However, Dr. Hunter identifies one important implication from this study that is likely to be robust when this study is published under peer review:

“One of the key implications of this is that those studies that have looked at the prevalence of [antibodies] in a population as an estimate of past infection […] will likely have substantially underestimated the proportion of people who have already had COVID-19 and recovered.”

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