Published On: October 17, 2023

ISGlobal researchers Carlota Dobaño and Gemma Moncunill lead the END-VOC work package on immunity

One of the most pressing questions in the early days of the COVID-19 pandemic revolved around the immune response to the novel coronavirus. Understanding the magnitude and duration of this response was imperative in guiding pandemic control measures in addition to developing effective vaccination strategies. Carlota Dobaño, Gemma Moncunill and their team at the Barcelona Institute for Global Health (ISGlobal) have been following the immune response to SARS-CoV-2 in various longitudinal cohorts for more than three years. In this interview, they provide some valuable insights into the factors that shape COVID-19 immunity.

We have monitored the immune response to SARS-CoV-2 with a depth and scale that we had probably never done with any virus before. Have we learned anything new? Any surprises compared to other respiratory viruses?

There have been no major surprises in what we already knew about the immune response to viruses. However, we have learnt much more about the role of antibodies in preventing infection, and about the key role of cellular responses in providing longer-lasting protection against disease.
Perhaps one surprise has been the heterogeneity of the immune response and how this determines the course and severity of the disease (from asymptomatic to severe or fatal cases). Some of this variability is explained by genetics. For example, genetic variants or defects in genes related to type I IFN (one of the key antiviral responses) that result in an impaired production or response to IFN, are associated with severe COVID-19. Similarly, the presence of autoantibodies against IFN has also been associated with severe disease. There are also non-genetic host factors such as previous exposure to related coronaviruses that cause common colds. Importantly, the pandemic has also allowed us to gather evidence of the negative effect of environmental factors such as air pollution and other pollutants on the immune response to infection and vaccines, highlighting the impact of the environment on our defences.
Another unexpected aspect of the pandemic was the relatively high incidence of long Covid or post-Covid syndrome and how debilitating this condition is. Post-viral syndromes have been reported for other viruses, but long Covid has raised awareness of how common they can be and on the need to understand the causes.

What do you think are the main questions that remained to be answered regarding immunity to SARS-CoV-2?

One of the major gaps in our knowledge is, precisely, understanding the causes of long Covid. This will allow us to identify specific biomarkers for early diagnosis and to develop much-needed treatments. We suspect that damaging immune responses are involved, but we still do not understand the exact role of the immune system in triggering or exacerbating the condition.

Another gap is identifying immune correlates of protection. In other words, immune markers that would help determine whether someone is protected or not. Vaccine-mediated immunity to infection is rather short-lived, so we need to understand how to generate longer-lasting immunity.

Another open question is the impact of the immune imprinting on the response to new SARS-CoV-2 variants. Immune imprinting, also known as antigenic sin, is a phenomenon whereby the initial immune response to a variant limits the ability to respond to new viral variants.  This is of paramount importance for designing new boosters.

Also of interest is understanding why African populations tended to develop less severe disease.  This could be partly due to the demographics, with a predominantly young population, but it does not explain everything. Some hypotheses point to differences in genetics, while others suggest that co-infections with other pathogens prevalent on the continent could modulate the inflammatory response to SARS-CoV-2 infection.

Hybrid immunity (vaccination plus infection) has been shown to be much more robust than either alone. Does this mean that it might also last longer?

It could be. We know that hybrid immunity induces higher levels of neutralising antibodies, which would take longer to decline to undetectable levels. But it is not just a matter of quantity. We also know that with each exposure to the virus (through infection or vaccination) the quality of the immune response improves (antibodies become better at recognising the virus) and this is also related to a more refined memory B cell response. There is however little evidence that the rate of antibody decay is different. We need more studies on the kinetics of the cellular arm of the immune response (memory B cells, antibody-producing plasma cells, and memory T cells).

As more and more people acquire hybrid immunity to the virus, do you think it is necessary to continue vaccinating?

People at higher risk of severe disease, such as those who are immunosuppressed or elderly, should continue to receive regular boosters, preferably with updated vaccines. People who care for or live with people at risk should also get boosted to reduce the likelihood of transmitting the virus. For the rest of the population, further boosters do not seem necessary at this time, given the high level of hybrid immunity that continues to protect against severe disease and death. However, this could change in the future if a new variant with increased virulence or immune escape emerges, or if the immunity that protects us against severe disease falls below a certain threshold. This is why it is important to continue to monitor the number of cases, hospitalisations and the emergence of new variants.

Do you consider that developing intranasal COVID-19 vaccines to prevent infection is an absolute priority, or are the intramuscular vaccines doing a good enough job by keeping most people out of the hospital?

Intranasal mucosal vaccines, if effective against infection, would help to control viral transmission and would be an added benefit to the current injected vaccines, especially if they also prevent severe and mild disease (which would be expected if infection is avoided in the first place). Mucosal vaccines could be particularly useful in protecting vulnerable populations which remain at risk even when the rest of the population has protective immunity against disease.  In addition, by reducing transmission, mucosal vaccines would reduce the likelihood of emergence of new variants of concern.  Finally, another thing to consider is that intranasal vaccines may be better accepted because no one likes needles and they are easier to administer. Their use, especially as boosters following intramuscular vaccination,  could therefore provide greater benefit for the population (preventing infection on top of disease).

We have all been focusing on antibody levels after vaccination or infection. But many immunologists agree that T cells have been the ‘unsung heroes of COVID-19 resistance’. Any thoughts on this? Can we further harness the power of T cells?

Indeed, neutralising antibodies act by blocking host cell infection, but once infection occurs, only T cells, alone or in cooperation with non-neutralising antibodies and cells of the innate immune system, can kill the virus-infected cells. Therefore, T cells of both types (CD4 and CD8 lymphocytes) are essential for protection against disease. They are also responsible for memory responses that remember the virus for a long time and fight it in case of reinfection.

Importantly, T cell responses recognise parts of the viral proteins that are conserved between variants. So, despite their ability to evade neutralising antibodies, the new variants are still recognised by T cells. This explains why, although we may no longer protected against infection, we are still protected against disease, especially severe disease.

The problem is that T cells are technically more difficult and expensive to study in the laboratory, and that is why we know less about them and how to harness their power in vaccination. This is surely another priority area for research.


Interview by Adelaida Sarukhan, scientific writer at ISGlobal and leader of ENDVOC’s Work Package on Dissemination, Exploitation and Communication