The rare flip-side of the immunological coin: Post-vaccine syndrome (PVS).

Vaccines are transformational medicines at the population level, saving millions of lives over hundreds of years. However, any medicine can carry rare individual risks.

This was not easy to write as I was incredibly worried what I said would or could be weaponised but I think its important to discuss. Huge thanks to comments and input from Steve Griffin, Christina Pagel and Duncan Robertson.

Vaccines against SARS-CoV2 have prevented million of deaths from COVID-19, dramatically reducing the risk of both severe acute illness and long-COVID. Estimates of the number of lives saved range upwards from 20 million in just the first year (2021), with an approximate reduction of potential deaths by 59% over the course of the pandemic. Notably, these were the first ever successful vaccines targeting a Coronavirus, whether in man or in animals. We were fortunate.

These vaccines have clearly been an enormous success story but, like all medicines, side effects are possible. This is especially important to understand as vaccines, unlike most medicines, deliberately engage our immune response to achieve their protective effects. As immunity is defined by our genes, a planet of seven billion genetically diverse human beings will inevitably include rare outcomes.

Predictably, with billions of doses administered since 2021, this has been the case for COVID-19 vaccines too. A very small fraction of the population have reported a chronic condition following immunisation – which has also been dubbed as post-vaccination syndrome (PVS). Critically, PVS is largely unrecognised by healthcare systems, leaving patients with limited options in terms of support and/or treatment.

What is PVS?

The incidence of PVS is low, even compared to other rare adverse vaccine reactions, which has made it difficult to study. For example, one study assessed just 3 patients with other reports involving single case studies. As such, the mechanisms underpinning why some responses lead to PVS are not well understood. There does, however, seem to be many similarities between the self-reported symptoms of long COVID and PVS. This may include, for example, clusters of symptoms spanning extreme fatigue, breathlessness, brain fog, neurological problems, cardiovascular issues, and joint pain, persisting for 12 weeks, or more. Logically, given that both infection and vaccination “programme” our immunity in similar ways, this may not be as surprising as it first sounds.

People with PVS had distinct immune signatures

A new pre-print from the Yale LISTEN Study compared 42 participants with PVS with no pre-existing comorbidities and 22 control subjects; 42 counts as the largest PVS study to date, illustrating how scarce PVS is. This low number also means there must caution to over-interpreting the data based on relatively low numbers. PVS was defined akin to the criteria used to define Long Covid i.e. a change in health status that began after the vaccine was administered and had not resolved within 12 weeks. The groups were further split into 4 groups, depending on whether the researchers could establish a prior history of infection using an antibody test (I) before the vaccination (this couldn’t be conclusively shown in everyone).

B. Stacked bar plots showing the number of males and females in the four subgroups. C. Scatter plots showing the distribution of age across subgroups. https://www.medrxiv.org/content/10.1101/2025.02.18.25322379v1.full.pdf

The researchers looked at what sort of immune cells (white blood cells) were present in the blood of these patients, how they were behaving, and which antibodies had been made. Similarly, they looked at what genes may have been switched on or off in these patients to understand the mechanisms at play. They also looked at how other infections, including other viruses, were behaving in people with PVS.

A. Summary of the study design, 602 cohorts and assays included in this study https://www.medrxiv.org/content/10.1101/2025.02.18.25322379v1.full.pdf

Overall, the picture was complex with the condition manifesting as multiple subgroups rather than a one-size-fits-all disease. Again, this is reminiscent (yet distinct in many ways) of long COVID. PVS groups predictably reported increased ill-health compared with controls, and were understandably less likely to have completed full COVID vaccine/booster courses and these were naturally further in the past. The number of vaccines correlated with the levels of anti-spike protein antibodies, and so were lower in PVS patients.

PVS groups showed differences in both their innate (non-specific) and adaptive (antigen-targeted) white blood cell responses. Monocytes, a type of innate white blood cell, were higher in PVS patients, likely indicating ongoing inflammation. By contrast, another innate cell type, conventional dendritic cells (cDC), were much lower, as were a type of adaptive cell called an effector memory CD4 T-cells (CD4em). This can indicate a “misfire” of the adaptive response, as cDC and CD4em cells help coordinate immune responses against specific targets of the virus. Accordingly, a type of T-cell that are needed to kill virally infected cells and viruses, cytotoxic T cells or CD8 T-cells, showed evidence of being “exhausted” - making them less effective at viral killing. This overall shows an immune response that has gone awry and is not working as it should. A hallmark of a less effective immune response is that so-called latent infections can re-emerge and this is exactly what was seen.

The researchers looked at Epstein Barr virus (EBV), a herpes virus that causes Glandular Fever. EBV is never fully cleared from our body and persists at low levels for life following infection held in check by our immunity. In several of the PVS patients, the EBV had been reawakened. This was indicated by increased production of antibodies that can target EBV. In addition, some of the PVS cohort had some evidence of antibodies reacting against their own bodies, so-called autoantibodies. Collectively this data paints a picture of an immune system that is misfiring.

Finally, PVS patients were more likely to have detectable, yet miniscule (a million-billionths up to 10 billionths of a gram per mL of blood), levels of spike protein along with their reduced levels of anti-spike antibodies. Interestingly, higher circulating Spike levels appeared to be positively linked with having previously experienced an infection.

PVS data had clear correlations with Long COVID immune features.

Interestingly, much of this data overlaps results from studies assessing Long COVID, which also show distinct immune signatures. For example changes in monocytes, adaptive cells (T and B cells), T cell exhaustion, reactivation of latent viruses such as EBV and persistent viral antigen are also evident in many people with Long COVID. It was also notable that somewhat more of the people with PVS in this study were women. Data has shown that Long Covid is more likely if you are female. Severity of infection is also a factor in likelihood of developing long COVID, but this was not assessed in this study.

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One important distinction with Long Covid studies is that people with co-morbidities were excluded from the LISTEN study, whereas this is a key predisposition towards developing Long Covid. The small group sizes for PVS make such data difficult to interpret though. Hence, although there may be similarities in the groups of people that are susceptible to both Long Covid and PVS we can’t really speculate if this is due to the same susceptibility factors and/or common mechanisms.

The observation of persistent, albeit low level, spike protein in PVS patients without prior infection is perhaps surprising to some; similarly low levels of spike protein are observed in some long COVID sufferers. However, the lower levels of spike-reactive antibodies in PVS again suggests that the immune response may have misfired, being unable to clear the protein generated by the cells, including monocytes (raised in this study), whose job it is to “present” the spike protein to the adaptive immune system. Another possibility is that all the individuals had had a prior infection. Previous infection was established by looking for the presence of antibodies to parts of the virus which is not completely unequivocal - as some people will not have a good antibody response so the possibility that all participants had prior infection cannot be excluded.

Another possibility is given the small sample size is that some of these features observed are down to chance. More studies are needed to confirm findings and look for mechanisms and consequences. Given the rarity of PVS this is challenging but cooperation across the world bringing together data sets may help.

What should we take away from this study?

First and foremost, this is to date the most comprehensive analysis of PVS and its incredibly important we look at this study and do not ignore it. Whilst the study is yet to pass peer review, people suffering with this albeit rare condition have been overlooked and deserve to have better treatments. PVS, much like long COVID and other conditions such as ME/CFS are complex consequences of how our immune responses behave. Our immune system is incredibly powerful but it does sometimes misfire, so the more we understand it, the better we can counteract its impacts when it goes awry. There is already greater focus and progress on these issues as we continue to learn from the pandemic, and this study further informs scientists on this mission.

However, this analysis should neither derail vaccine development, nor be weaponised to support anti-vaccine disinformation campaigns. We must remember that rare individual adverse reactions are balanced against the population-scale benefits that vaccines bring. It is not correct or rational to simply compare outcomes with/without a vaccine, but to the impact of a disease being allowed to run rampant, unchecked. COVID vaccines have broken the link between infection and severe disease for the majority of the population, something that really ought not to be taken for granted.

Improved understanding of PVS and other conditions should lead both to new ways of tailoring how we give medicines to avoid people developing severe reactions, as well as to develop treatments for those who do. This is only realistically possible for rare events when vaccines or other medicines are given at scale, such that enough rare cases can be compared and action can be taken to avoid problems in the future. Examples include the tragic but rare cerebral blood clots caused by the AZ vaccine, or reactions to the immunosuppressive drug, azathioprine, understanding of which led to a newly available test to determine its suitability for patients.

Ultimately, any medicine is an intervention and it’s critical to monitor safety both during development as well as through ongoing clinical use to ensure that benefits outstrip potential harms. Public health must act both in the interests of the population as well as to support the individual, and this can only be achieved through scientific rigour and honest interpretation of an ever-evolving wealth of data.

The vaccines for Covid19 saved millions of lives and reduced the risks of severe disease and long Covid and this must not be forgotten. These vaccines continue to be an invaluable tool to help tackle Covid19 which continues to evolve and is ever pervasive. PVS is incredibly rare and affecting a tiny minute fraction of the millions of those who have been vaccinated. Nonetheless the more we understand about PVS, the more we can help people who have it and the more we can try ways to prevent it in future. This is why it’s important to study it BUT bad faith people are misrepresenting the study. Don’t listen to them.