New insights into immune responses

COVID studies led by Professor David Lynn Director, Computational and Systems Biology Program Lynn Systems Immunology Group at South Australian Health and Medical Research Institute (SAHMRI) and Professor of Systems Immunology at Flinders University, have identified new insights into COVID-19 immunity and Long COVID.

The COVID-19 Vaccine Immune Responses Study (COVIRS), led by Flinders University and SAHMRI, uncovered fundamental differences in how the AstraZeneca and Pfizer COVID-19 vaccines impact the immune system.

The study tracked the immune responses of 102 adults of varying ages living in South Australia immediately after receiving either the Oxford/AstraZeneca or Pfizer/BioNTech COVID-19 vaccines to assess early immune response.

They were also tested 28 days after every immunisation to evaluate B and T cell activity.

Professor Lynn said the study used a method of biological analysis known as ‘multiomics’ to examine immune responses in many different ways in thousands of blood samples.

Researchers were surprised to find that the Oxford/AstraZeneca vaccine elicits an unexpected memory-like response in the immune system after the first dose, recognising the vaccine as if it’s something it has seen before.

‘This response is targeted against the adenovirus vector in the vaccine, not the Spike protein and the intensity of this response correlates with the expression of proteins that act as a pre-cursor to thrombosis, or blood clotting.

‘While vaccine-induced immune thrombotic thrombocytopenia (VITT) is an extremely rare side effect associated with the Oxford/ AstraZeneca vaccine that none of the participants developed during the study, this research offers a potential explanation for the connection between the Oxford/AstraZeneca vaccine and the cases of VITT that have been reported,’ said Professor Lynn.

The study also found those who had only had two doses of the Oxford/AstraZeneca vaccine generally produced lower amounts of antibodies and less of a specialised type of T-cell that helps with antibody production compared to those who had two doses of the Pfizer/BioNTech vaccine.

This was rectified once they had their third booster dose of an mRNA vaccine, illustrating the importance of booster doses.

The study added evidence to the notion that COVID-19 vaccines offer some people more effective protection than others.

Older people generally have a lower immune response after two doses but a third booster dose is highly effective at overcoming this.

Immune responses induced immediately after vaccination predicted the subsequent B and T cell response to the vaccine measured a month later.

“One to two days after initial vaccination we measured gene expression responses in the blood which correlated with adaptive immune responses that mediate protection 28 days later,” Professor Lynn explains.

A further surprise to researchers was the finding that people who showed symptoms of fatigue and fever immediately after the third dose were more likely to have better T-cell responses.

Study shows no evidence of trained immunity

Other researcher led by Professor Lynn has found no evidence that two doses of Covid-19 vaccines leads to trained immunity (TI) against the virus.

Trained Immunity (TI) is defined as the long-term metabolic and epigenomic reprograming of innate immune cells, priming them for enhanced responses to subsequent challenges, including unrelated infections.

The study explored whether two doses of two doses of the BNT162b2 (the Pfizer/BioNTech mRNA vaccines) or ChAdOx1-S (Oxford-AstraZenica) vaccines induced altered innate immune responses or epigenomic changes consistent with TI in a cohort of

46 healthy adults. Baseline characteristics of ChAdOx1-S (n=13) and BNT162b2 (n=33) recipients were not significantly different.

This followed other studies that suggested ChAdOx1-S but not BNT162b2 vaccination induces TI.

The SAHMRI data suggest that long-term TI is not induced in human PBMC or circulating classical monocytes following two doses of either the ChAdOx1-S or BNT162b2 vaccines.

The authors note further investigation is needed to assess whether these vaccines have any effects on TI induced in 4 cell-types not analysed here (e.g. granulocytes). The data from this study are consistent with the conclusion that BNT162b2 vaccination does not induce long-term epigenetic reprogramming of monocytes.

Data suggest that any effects of these vaccines on TI after one dose are transient and not induced after a second dose, which is important given that the vast majority of people have received these vaccines as multi-dose regimens.

The findings therefore have important implications for current and future mRNA and adenoviral-vectored vaccines and support the safety of these vaccine technologies, the researchers say.

Long COVID insights

And a world-leading research collaboration in South Australia has delivered crucial insight into the lasting immune system dysregulation caused by COVID-19.

The study, conducted by experts at SAHMRI, Flinders University, the University of Adelaide, the Women’s and Children’s Hospital and the Royal Adelaide Hospital, showed that immune cells and gene expression experienced during the 6-month post-infection period hold clues to Long COVID.

The latest study results, published in BMC Medicine, indicates Long COVID could be linked to lower blood platelet count, with patients showing signs of thrombocytopenia (low platelet count) at six months post-infection compared to those who didn’t suffer Long COVID symptoms.

The research team profiled the immune systems of 69 people aged between 20 and 80 years old who contracted the original Wuhan strain of COVID-19, over a 6-month period post infection.

Of the total cohort, 47 were recovering from mild infection, 6 from moderate and 13 were recovering from severe or critical disease.

Around one-third expressed symptoms associated with Long COVID and were referred to a Long COVID clinic.

Professor Lynn says the research found persistent mild thrombocytopenia in people with Long COVID and one of the most common side effects of this condition is fatigue, which is also the primary symptom of Long COVID.

Most study participants showed significant immune system dysregulation for at least 12 weeks post infection, though the majority returned to normal levels by 24 weeks.

‘The level of disease severity doesn’t translate directly to the level of immune dysregulation and we haven’t been able to find any patterns indicating that an individual’s age or sex is a differentiating factor governing differences in recovery.

‘Clearly there are other factors at play that need to be explored,’ Professor Lynn says.

‘At this stage we’ve only been able to analyse data from the original strain of the virus, so it’s not possible to say how Delta and Omicron may vary the immune system response.’

The longitudinal analysis examined antibody responses, the expression of thousands of genes in the blood, and approximately 130 different types of immune cells, that were compared to healthy controls.

As well as a substantial increase in the number of immune cells and antibodies, researchers found there was also strong dysregulation of gene expression, particularly in those genes linked to inflammation.

The study has also added further evidence that those who have had COVID-19 develop some immunity to the virus.

Participants antibody titers indicated a high level of immunity for at least six months post infection, but it’s unknown whether the same result would be true for those who contract other strains.

Researchers will continue to follow the participants for three years to document how the immune system continues to respond long term.

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