Reinfection

CDC Study Claiming Unvaccinated Have More Than Double the Risk of Re-infection is Full of Holes

The Centers for Disease Control and Prevention (CDC) in America has published a new study claiming to show that, among the previously infected, the unvaccinated are at more than double the risk of re-infection than the vaccinated.

It forms part of their evidence for why people who have had COVID-19 before should get vaccinated and not rely on natural immunity.

It has a number of problems, however.

The study looks retrospectively at data from the U.S. state of Kentucky. The researchers identify all those in the state who were re-infected during May and June 2021 (defined in terms of positive tests a certain number of days apart) and compare their vaccination rates to a control group. They find 246 re-infections in that period, and calculate that those who were not vaccinated were 2.34 times more likely to be re-infected than those who were vaccinated.

The study has a number of limitations, however, some of which the authors acknowledge.

Firstly, the study period of May and June 2021 is notable for being a period of very low prevalence in the state, meaning it is not a good time to study acquired immunity, which is best studied during a new surge when it is most put to the test. The authors themselves acknowledge that because the study covers just one period in one state, the “findings cannot be used to infer causation”.

The authors also acknowledge that test-seeking behaviour may skew the findings to exaggerate vaccine effectiveness, as vaccinated people are probably less likely to get tested.

Another weakness is that the study doesn’t include symptom data so we don’t know whether the “reinfections” were actual disease or just asymptomatic and mild infections of the kind that are characteristic of the immune system working.

A related problem is that there is no discussion of how big the problem of re-infection is from an absolute standpoint. With only 246 re-infections (of unknown severity) in a population of 4.5 million over a two month period, it’s not clear that even if vaccination did halve your probability of re-infection it would be a difference worth getting vaccinated (which carries its own risks) to achieve.

Reports of Reinfection With the Delta Variant are Greatly Exaggerated

There are reports today that the Delta variant is much more likely to reinfect people than the Alpha variant. The Telegraph has the story.

People who have previously caught Covid are now more likely to be reinfected because of the delta variant, a study has found.

Laboratory analysis revealed that the mutation that originated in India is four times more able to overcome protective antibodies from a previous infection compared to the U.K.’s alpha variant.

The study also found that a single dose of either the Pfizer or AstraZeneca vaccines provided just 10% protection against the delta variant.

The variant was already thought to be up to 60% more infectious than the version which swept the U.K. last winter.

The findings, published in the journal Nature, help explain why the virus is spreading so quickly, particularly among younger adults, fewer of whom are double-vaccinated.

It’s important to be aware that this is just a set of laboratory tests on one virus sample. It involves no examination of real world reinfection rates.

Furthermore, it only tests antibodies, not T cells, so is not giving a full picture of the immune system’s response. As the authors admit, one limitation of the study is “the lack of characterisation of cellular immunity, which may be more cross-reactive than the humoral response”.

The claim that a single dose of the vaccines only gives 10% protection against infection with the Delta variant is also not based on any measurement of real world infection rates but on how many of the antibody blood samples “neutralised” the virus in the virus sample. While it may be true that one dose of the vaccines gives limited protection against the Delta variant, this is not the way to quantify it.

The study argues its findings suggest the need to vaccinate those previously infected to boost their immunity: “These results strongly suggest that vaccination of previously infected individuals will be most likely protective against a large array of circulating viral strains, including variant Delta.”

However, without studies on cellular immunity and real world reinfection rates such a conclusion would be very premature.

Real world data suggests the threat is overblown. Public Health England today reports on the latest reinfection data from the SIREN study of healthcare workers, stating that “reinfections remain at very low numbers in individuals previously either PCR positive or seropositive”. There have been just 16 potential reinfections between April and June 27th in the 44,546 people in the cohort, of which over 9,800 have confirmed previous infections. While 95% of the group are fully vaccinated, only one of the 16 possible reinfections was in the 5% who are unvaccinated. This strongly suggests the real world risk of reinfection, whether vaccinated or unvaccinated, is very small.

Vaccination Doesn’t Add Any Protection to that Gained from Previous Infection – Study

A new study (not yet peer-reviewed) of over 50,000 employees of the healthcare system in Cleveland, Ohio, has found that previous infection provides very robust protection against re-infection and, importantly, that there is no gain to being vaccinated as well.

U.S. Senator Rand Paul tweeted the study’s conclusion: that it means vaccines should be prioritised for the not-previously-infected at home and abroad, not wasted on the already immune.

The confirmation of the protection provided by natural infection is very welcome, as is the finding that vaccinating the previously infected is superfluous. Given the significantly higher risk of adverse events for those previously infected (up to three times higher according to the ZOE Lancet study) and the world shortage of vaccines, there would seem to be a moral imperative to cease vaccinating the previously infected.

The study’s finding is particularly robust because of the large sample size and because there were zero instances of re-infection among the previously infected (both vaccinated and unvaccinated). This was despite the study period beginning at the peak of Ohio’s winter wave, so the unvaccinated had plenty of exposure to the virus. Other studies have found the relative risk reduction offered by previous infection to be 80% against all re-infection and 90% against symptomatic re-infection, so the results in this study were even higher than usually observed.

However, the study’s findings for vaccine effectiveness in the not-previously-infected are much less reliable.

You Can Catch Covid Twice – But it’s Very Rare and Very Mild

Can you catch Covid twice? The challenge trials at Oxford University have now turned their attention to this question, deliberately exposing people who have had the disease before to the virus again to see how their immune systems respond.

Other studies have already looked into this question, though without the controversial deliberate exposure aspect. The most recent, published in the Lancet last week, tested around 3,000 U.S. Marine recruits aged 18-20 for Covid antibodies and then followed them over six weeks while they completed basic training together to see how many became infected. The living in close quarters would likely have ensured that all were exposed to the virus.

The study found that around 10% of seropositive (with-antibodies) participants (19 out of 189) tested PCR positive for the virus versus around 50% of seronegative participants (1,079 out of 2,247). This means that having antibodies from a previous infection gives about 80% protection from testing positive for the virus again. This finding closely matches that of a large Danish study published last month, that found those who had tested positive for the virus in the spring were about 80% less likely to test positive again in the autumn. And also a UK study of NHS workers from January that found being PCR positive for the virus at one point made workers around 80% less likely to test positive again at a later date.

The new study was being used last week to promote the idea of vaccinating young people who had previously been infected, on the grounds that protection via infection was not enough. Thus Sky News reported: “Young people who have already tested positive for coronavirus are not fully protected against reinfection.”

The study itself supported this use, stating its results suggest “COVID-19 vaccination might be necessary for control of the pandemic in previously infected young adults”. Professor Stuart Sealfon of Icahn School of Medicine at Mount Sinai, New York, and senior author of the study, said:

As vaccine rollouts continue to gain momentum it is important to remember that, despite a prior COVID-19 infection, young people can catch the virus again and may still transmit it to others. Immunity is not guaranteed by past infection, and vaccinations that provide additional protection are still needed for those who have had COVID-19.

What such claims appear not to allow for is that questions are being asked about how the balance of risks stacks up for young people to be vaccinated even when they have not had Covid, let alone when they have and have 80% protection already. To this balance must be added that severe side-effects are considerably more common in those who have previously had Covid.

The 80% protection figure is also not the full story on immunity following infection. Noteworthy is that symptomatic infection was much less common among those who had antibodies. In fact, only three out of 19 (16%) seropositive PCR positives were symptomatic, versus 347 out of 1,079 (32%) seronegative PCR positives. The large proportion of PCR positive infections that are asymptomatic even among those without antibodies (68%) may be an indication of the high degree of pre-existing immunity among the young.

The infections among those with antibodies were also much less likely to be infectious, with average Ct of 27-28 versus around 24 for the seronegative infections (Ct or cycle threshold corresponds inversely to viral load, which corresponds to infectiousness). This translates to a viral load about ten times lower, which is considerably less infectious.

U.K. Trial Launched to Deliberately Infect People with Covid after They’ve Already Had It

Researchers at the University of Oxford have launched a trial that will deliberately expose people who have already had Covid to the coronavirus again to study the level of immune protection needed to prevent reinfection (assuming reinfection is possible). It is hoped that the study will aid the development of treatments and vaccines. The Guardian has the story.

The first human challenge trials for Covid began this year, with the study – a partnership led by researchers at Imperial College London among others – initially looking at the smallest amount of virus needed to cause infection among people who have not had Covid before.

Now researchers at the University of Oxford have announced that they have gained research ethics approval for a new human challenge trial involving people who have previously had coronavirus. Recruitment is expected to start in the next couple of weeks.

“The point of this study is to determine what kind of immune response prevents reinfection,” said Helen McShane, a Professor of Vaccinology at the University of Oxford, and Chief Investigator on the study.

McShane said the team would measure the levels of various components of participants’ immune response – including T-cells and antibodies – and then track whether participants became reinfected when exposed to the virus.

Participants must be healthy, at low risk from Covid, aged between 18 and 30, and must have been infected with the coronavirus at least three months before joining the trial. As well as having previously had a positive Covid PCR test, they must also have antibodies to Covid. Given the timing criteria, McShane said it was likely most participants would have previously been infected with the original strain of the virus.

The first phase of the trial will initially involve 24 participants split into dose groups of three to eight people who will receive, via the nose, the original strain of coronavirus. The idea is to start with a very low dose and, if necessary, increase the dose – up to a point – between groups…

The second phase of the study – expected to start in the summer – will involve a new group of participants and will study closely their immune response before and after exposure to the virus, as well as the level of virus and symptoms in those who become reinfected.

The vaccines which produce the required level of immunity – as determined by this study – could have their licensing fast-tracked without trials of thousands of people, according to Professor McShane.

If we can determine the level of immune response above which an individual cannot be infected, then that will help us determine whether new vaccines will be effective without necessarily having to test them in phase three efficacy trials.

Worth reading in full.

Lancet Paper Flagging Up Risk of Reinfection is Garbage

We’re publishing an original piece today by Mike Hearn, the former Google software engineer who is the author of this site’s most read piece. (He used to contribute under the name Sue Denim, but has since come out.) It’s a review of a recent paper in the Lancet purporting to show that 20% of Danes infected in Denmark’s first wave became reinfected in the second wave. As Mike reveals, this conclusion was based on assuming the false positive rate of the PCR test is much lower than the researchers had any reason to assume. Here are the first three paragraphs:

A recent paper in the Lancet claims that one in five people might not get immunity from being infected with COVID. The study is invalid. Although these sorts of problems have been seen before, this is a good opportunity to quickly recall why COVID science is in such dire straits.

The research has a straightforward goal: follow a population of Danish people who tested positive in Denmark’s first wave, and re-test them during the second wave to see if they became infected a second time. Denmark has a large free PCR testing programme so there is plenty of data to analyse. Out of 11,068 who tested positive in the first wave, 72 also tested positive during the second wave. This fact is used to advocate for vaccination of people who’ve already had COVID.

The obvious problem with this strategy is that false positives can cause apparent reinfection even when no such thing has happened. The paper doesn’t mention this possibility until page 7, where the entire topic is dismissed in a single sentence: “Some misclassifications by PCR tests might have occurred; however, the test used is believed to be highly accurate, with a sensitivity of 97·1% and specificity of 99·98%.” My curiosity was piqued by this figure because, as I’ve written about previously, at least as of June last year nobody knew what the false positive rate of COVID PCR testing is. The problem is circular logic: COVID is defined as having a positive test, therefore by definition it has no false positives, even though we know this cannot be true.

Worth reading in full.

Stop Press: The New York Times reports on a new study showing that eight months after infection most people who have recovered from coronavirus still have enough immune cells to fend off the virus and prevent illness. A slow rate of decline in the short term suggests that these cells may persist in the body for a very, very long time to come.

Review of Paper Claiming 20% of Infected Are Vulnerable to Reinfection

by Mike Hearn

A recent paper in the Lancet claims that one in five people might not get immunity from being infected with COVID. The study is invalid. Although these sorts of problems have been seen before, this is a good opportunity to quickly recall why COVID science is in such dire straits.

The research has a straightforward goal: follow a population of Danish people who tested positive in Denmark’s first wave, and re-test them during the second wave to see if they became infected a second time. Denmark has a large free PCR testing programme so there is plenty of data to analyse. Out of 11,068 who tested positive in the first wave, 72 also tested positive during the second wave. This fact is used to advocate for vaccination of people who’ve already had COVID.

The obvious problem with this strategy is that false positives can cause apparent reinfection even when no such thing has happened. The paper doesn’t mention this possibility until page 7, where the entire topic is dismissed in a single sentence: “Some misclassifications by PCR tests might have occurred; however, the test used is believed to be highly accurate, with a sensitivity of 97·1% and specificity of 99·98%.” My curiosity was piqued by this figure because, as I’ve written about previously, at least as of June last year nobody knew what the false positive rate of COVID PCR testing is. The problem is circular logic: COVID is defined as having a positive test, therefore by definition it has no false positives, even though we know this cannot be true.

Is it possible this problem has been fixed? Sadly we’re talking about public health, so the answer is no. The citation is deceptive. The cited paper is from August and is a modelling paper. When read carefully we discover two surprising facts: firstly, the conclusion says clearly that “A high risk of false-positives should be considered… This may have consequences for, e.g., containment strategies and research”. In other words, the opposite of what the Lancet study tries to imply it says. And secondly, the 99.98% figure is totally made up:

[W]e set specificity to 99% – the lower level suggested by the Danish Health Authority. However, this figure may be an underestimate. Cross-reactivity to other endemic respiratory viruses has not been found under reference conditions. Contamination etc. are minimised by strict procedures in clinical practice. We therefore also repeated the analyses using a higher specificity of 99.98%…

In other words, although the government tells them to expect a 1% FP rate, they decided they felt more optimistic by nearly two orders of magnitude. No justification for the 99.98% specificity figure is provided beyond their faith in “strict procedures”. It’s pulled out of thin air and used as an alternative model scenario. To get the number of “reinfections” in the Lancet study only requires an FP rate of ~0.65% so actually, if the Danish government’s advice is correct, we should expect all the reinfections to be false positives. Certainly, no useful evidence is provided that it’s not the case.

I think most of us have stopped being surprised by this sort of thing. Papers with severe problems that literally anyone can find in five minutes keep being published by major journals. Worse, this particular issue is so basic it’s hard to see how it could be a mistake. Although it’s painful to reach, the only plausible conclusion is that scientists know they are misleading people and are doing it deliberately out of a misguided belief that it’s for the greater good.

Finally, please remember that a paper being invalid does not automatically prove the inverse claim is true i.e., the takeaway here is not “being infected always grants immunity”, even though that seems rather likely, but only that this paper doesn’t prove the opposite.

Mike Hearn is a former Google software engineer. You can read his blog at Plan 99.