November 9, 2021

expert reaction to press release from the ZOE COVID Study suggesting ‘COVID infection doesn’t guarantee antibodies’

The press release from the ZOE COVID Study states that not all participants who took an antibody test after a known COVID-19 infection tested positive for anti-N antibodies (those acquired from a natural infection). 

Dr Julian Tang, Honorary Associate Professor/Clinical Virologist, Respiratory Sciences, University of Leicester, said:

“These results are rather simplistic and incomplete.  There is no assessment of T cell responses or mucosal IgA responses – and importantly the timing of the antibody tests relative to infection.  There is a wide range of variability in the timing of antibody responses in individuals – which may matter if only one sample is taken at one time point: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902674/#!po=0.819672.

“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: https://www.frontiersin.org/articles/10.3389/fimmu.2021.687449/full; https://www.sciencedirect.com/science/article/pii/S2666379121002032; https://www.nature.com/articles/s41577-020-00436-4; https://www.cell.com/cell/fulltext/S0092-8674(20)31008-4; https://www.nature.com/articles/s41467-021-22036-z.

“And of course natural infection (as with other viruses) will produce a whole spectrum of antibody responses to the other viral proteins – even if not many studies have examined these, such anti-E, anti-M, anti-RdRp, etc. (https://www.sciencedirect.com/science/article/pii/S2211124721007890) including neutralising anti-S antibodies that are not examined here – that can also provide immune protection that are not assessed in this ZOE study.  This is why natural infection with viruses generally provides longer lasting and broader immune protection – compared to vaccination.

“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:

https://www.nejm.org/doi/full/10.1056/nejmoa0906453.”

Dr Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said:

“Whilst this is a press release rather than a submitted/published study, the findings – assuming they are representative of the population as a whole – are of vital importance when considering current COVID policy, in particular the increasingly widespread misrepresentation that becoming infected with the virus is somehow preferable to protection via vaccination.  This is neither a pre-print, nor a peer-reviewed study, and so these interpretations may be subject to change in light of future developments.  However, combining the ZOE app with real-world serology is a powerful means by which to monitor the impact of SARS-CoV2 infection, and it is always vital to act quickly, and upon the latest available information when dealing with an epidemic of infectious disease.  Thus, whilst the precise numbers might change upon further study, the high levels of patients failing to develop anti-N antibodies is unlikely to be explained by anything other than an incomplete immunological response to infection.

“The ZOE data is consistent with other past studies where a positive correlation between disease symptomology/severity and ensuing immune responses exists.  Worryingly, around one in five individuals appear not to make any discernible anti-N antibodies following confirmed infection with SARS-CoV2.  Moreover, patients who smoke or suffer additional comorbidities are even less likely to generate an anti-N antibody response, whilst being those most vulnerable to severe disease.

“Whilst those with responses appear to show long-lasting antibodies, the risk of experiencing a potentially life-threatening infection to become immune to that same infection is, clearly (and as anyone might sensibly predict), utterly nonsensical when safe and effective vaccines exist.  Carts and horses spring to mind.

“Notably, whilst not included in this study, one population where severe disease with “classic” SARS-CoV2 symptomology (shortness of breath, fever, cough) is less common, and yet are only partly/not currently protected by the vaccine programme, is younger teenagers and under 12s.  It has even been suggested by some that children are better experiencing direct infection than receiving vaccines.  COVID is not benign in children, whilst the relative risk compared to adults is of course smaller.  I find the notion that children are being exposed to a new, relatively uncharacterised virus without such protection genuinely dumfounding.

“Indeed, previous published studies have also supported that children are less likely to develop immunity following infection, and the observation that this can also occur in adults would seem to corroborate this.  The incredibly high levels of infection within our younger population therefore will not likely result in high levels of protective immunity, and similarly carries risks for those exposed as a result, including children and the adults with whom they are in contact.  Thus, any sort of herd immunity-by-infection strategy is, to my mind both ethically and scientifically devoid of any merit whatsoever.

“I wholly concur with the message from Prof Spector and Dr Steves that everyone offered a vaccine should accept the full course, and I would add that this should be done for as much of the UK population as possible.  The need for urgent vaccine coverage is driven by high, unmitigated virus prevalence, which also leads to more long COVID, and the effective isolation of clinically vulnerable members of society.  I hope that those considering the future course of the UK epidemic policy will now accept that mass infection should never have been, nor should be, a morally acceptable or effective way to manage SARS-CoV2.”

Dr Simon Clarke, Associate Professor in Cellular Microbiology, University of Reading, said:

“The observation that not everyone who has had a confirmed case of Covid-19 has antibodies to the virus would be extremely interesting if the authors had checked to see whether antibodies to the virus’ other structural proteins were missing too.  But judging from this press release, which does not appear linked to a peer-reviewed paper, they seem not to have done so.  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.

“Instead ZOE appear to have looked solely at antibodies to the N-protein, which is found predominantly within the core of the virus and is not exposed on its surface like the spike protein is.  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.  These questions are much easier to answer with something on the virus surface.

“Because we don’t really have a great understanding of how effective anti-N-protein antibodies are in protecting against Covid-19, it can’t be said that lacking them renders someone vulnerable to infection or disease and simple measures of antibodies in someone’s blood are rarely a good measure of protection.  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.

“While this reported lack of antibodies in some people is an interesting phenomenon which should be investigated more closely, its finding remain conjecture.  There seems to be a lot more work to do and I look forward to reading a peer reviewed study which would address possible alternative outcomes and explanations, in due course.”

Prof Paul Hunter, Professor in Medicine, UEA, said:

“The fact that people do not necessarily generate antibodies following COVID infection or indeed following vaccination is well known.  This paper by Wei https://www.nature.com/articles/s41467-021-26479-2 found that 24% or participants didn’t develop antibodies to the spike protein after infection.  This paper by Eslande https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891078/ looked at nucleocapsid antigen and also found 22.2% of mild and 2.6% of severe cases did not produce anti-N antibody.  Even in people who do develop antibodies such antibodies decline and may disappear over the following months.  In the Eslande study 61% of people who had just a mild illness or were asymptomatic were Ab negative within 6 months.

“Antibodies are not essential for recovery from covid and even people who have a primary immunodeficiency making it difficult for them to produce antibodies can have mild illness and recover from covid https://www.frontiersin.org/articles/10.3389/fimmu.2020.614086/full.

“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.

“People are more likely to remain Ab negative or become Ab negative sooner if they are older or have suffered a mild illness.  Given that younger people and children have milder and more often asymptomatic infection it is difficult to be certain about the exact proportion of different age groups who will not develop antibodies in the general population.

“One of the key implications of this is that those studies that have looked at the prevalence of antibody in a population as an estimate of past infection such as the UK REACT-2 and ONS infection Ab survey will likely have substantially under-estimated the proportion of people who have already had covid and recovered.”

Press release title: ‘COVID infection doesn’t guarantee antibodies’. There is no paper.

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Dr Stephen Griffin: “No conflicts.”

None others received.