Phd in ADVANCES IN INFECTIOUS DISEASES, MICROBIOLOGY, LEGAL
MEDICINE AND PUBLIC HEALTH SCIENCES

Thesis title: Dynamic changes in the functional profile of T-cell response to vaccination in PLWH

People living with HIV (PLWH) are at increased risk to suffer from pneumonia and other respiratory diseases, some cancers and coinfections, and related complications are more common and persistent in this population. Furthermore, they may experience a higher burden of various comorbidities. For these reasons, they are often designated as a priority group for different vaccinations. In general, the effective control of viremia with ART and a restored CD4 T cell count are correlated with an improvement of responsiveness to routine vaccines. However, efficacy of vaccines in this group is variable, due to the immunological changes and persistent immune dysfunctions that characterize the disease. In addition, the presence of comorbidities and coinfections may contribute to alter it. In this work, we investigated the immune responses to two different vaccinations in the setting of HIV infection, emphasizing the quality of the T-cell response. This aspect of the immune response, that refers to the combination of functions that T-cells are able to exert, is not extensively studied, although a higher degree of multifunctionality has been associated with higher protection. When I started my PhD, there was an urgent need to better characterize the immune response against the new mRNA-based vaccines against SARS-CoV-2 in vulnerable populations, including PLWH. In fact, the potentially worse outcomes of SARS-CoV-2 infections in this population and the risk that the vaccine-induced immune response to SARS-CoV-2 could be inferior or altered, has led the scientific community to pay great attention on this topic. In addition, reports regarding the immune response in PLWH were not always in accordance, and information about the quality of T-cell response in this population was not available. Therefore, our study aimed to contribute to clarifying the knowledge gaps in the understanding of the quality, magnitude, and duration of immunity to SARS-CoV-2 vaccination in PLWH, aspects that are critical for the proper application of mitigation strategies, including additional dose strategies. Collectively, our data supports that mRNA vaccination is able to elicit a humoral and cellular immune response against SARS-CoV-2 in most PLWH receiving ART, and that the booster dose enhanced the magnitude of these responses particularly among PLWH with a lower CD4 cell count. However, we found a particular signature in the functional profile of the T- cell response, that indicated a different quality of the response, with respect to the healthy donors. During the second part of my PhD, thanks to an initiative aimed at implementing vaccinations in target populations with an active friendly vaccination offer methodology held at the SM Goretti Hospital, I had the opportunity to investigate the immune response to another vaccination, the vaccination against HPV. For the primary prevention of HPV-related diseases, in 2014 the FDA approved Gardasil-9, an adjuvanted recombinant nonavalent vaccine, which recently, also has been introduced for the immunization of PLWH, regardless of age. Since most studies focus on the antibody response and bivalent and quadrivalent vaccines, we decided to focus our attention on the characterization of the adaptive immune response to the nonavalent Gardasil vaccine in a cohort of PLWH on ART, with a focus on the functional profile of T cells. Our study confirms that the vaccine is able to elicit a broad and coordinated immune response in our population, the benefits that people with a history of HPV infection might receive from vaccination and, finally, that PLWH with a lower current CD4 cell count remains a group who may not mount a fully protective immune response and, therefore, may require additional protection or ad hoc vaccination strategies. Results from conducted research on two very different vaccines in two different settings of PLWH were presented and discussed. However, in our opinion, it’s possible to draw some final remarks. Specific subgroups of PLWH can benefit from ad hoc immunization strategies, such as an adapted vaccine schedule, additional doses or use of adjuvants to improve immunological responses in order to achieve a proper level of immunization and, in this regard, the analysis of the functional profile of the T-cell response can represent a useful tool to capture some aspects of the immune response that may help guide us through this process. CC BY-NC-SA