Evaluation of Immunogenicity and Safety of 20-Valent Pneumococcal Conjugate Vaccine During Acute Febrile Illness in Adults at Risk for Pneumococcal Infection

The primary objective of this study is to demonstrate that the **immune response** at one month following the administration of the 20-valent pneumococcal conjugate vaccine (PCV-20) during an acute febrile illness is non-inferior to the immune response observed one month after PCV-20 administration 15-58 days post-resolution of the acute febrile illness. This is clinically relevant as it evaluates the potential flexibility in vaccination timing for unvaccinated patients at high and medium risk for pneumococcal infections, potentially improving vaccination coverage and outcomes.

Secondary objectives include:

• Comparing the safety of PCV-20 administration during an acute febrile illness versus 15-58 days after illness resolution at one month post-vaccination.
• Evaluating the impact of PCV-20 injection during an acute febrile illness on seroconversion in PCV-20 serotypes.
• Comparing functional immune response by opsonophagocytic activity (OPA) one month after PCV-20 administration during an acute febrile illness versus post-resolution.
• Comparing the immune response one year after PCV-20 administration during an acute febrile illness versus post-resolution.
• Evaluating the incidence of low respiratory tract infections one year after inclusion in both arms.
• Evaluating the incidence of laboratory-confirmed **Streptococcus pneumoniae** infections until one year after inclusion.
• Evaluating the impact of the gut microbiota on the immune response in both arms.
• Evaluating the reactogenic inflammatory response after vaccination in both arms.
• Comparing cellular immune response at one month and one year after PCV-20 administration during an acute febrile illness versus post-resolution.
• Comparing circulatory IgA level at one month after PCV-20 administration during a febrile illness versus post-resolution.

The clinical trial involves **participants** aged between 18 and 84 years, encompassing both male and female subjects. The study population includes individuals with a history of body temperature ≥ 38°C measured at least twice prior to randomization, and those with at least one comorbidity that categorizes them as medium or high risk for pneumococcal invasive infection. These comorbidities include conditions such as chronic heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and individuals living with HIV, among others. Participants must have been hospitalized for more than 24 hours and possess social security affiliation. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. The selection criteria ensure that the study focuses on unvaccinated patients at medium or high risk for pneumococcal infections, with the aim of evaluating the immune response to the 20-valent pneumococcal conjugate vaccine (PCV-20) administered during or after an acute febrile illness.

The clinical trial is designed to evaluate the **immunogenicity** and safety of the 20-valent pneumococcal conjugate vaccine (PCV-20) in adults with medium or high risk for pneumococcal invasive infection. This is a multicenter, randomized, non-inferiority trial with a double-blind, controlled design. The trial aims to demonstrate that the immune response at one month after PCV-20 administration during an acute febrile illness is non-inferior to the response obtained when the vaccine is administered 15-58 days after the resolution of the illness. The trial is expected to commence recruitment in December 2024 and conclude by October 2028, with participant involvement lasting up to one year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (18-84 years), history of fever, and presence of comorbidities that increase the risk for pneumococcal infection. Following randomization, participants will receive the vaccine via **intramuscular injection**. Follow-up visits will occur at one month and one year post-vaccination to evaluate primary and secondary endpoints, including the proportion of immune "good responders" and the safety profile of the vaccine. The end-of-study visit will mark the completion of the participant's involvement in the trial.

Participants may be withdrawn from the study early if they experience severe adverse events, withdraw consent, or if the investigator deems it necessary for safety reasons. The primary endpoints focus on the proportion of immune "good responders" at one month post-vaccination, defined by seroconversion and an immune protective response. Secondary endpoints include safety assessments, immune response kinetics, and the frequency of specific immune cells. The trial is categorized as low-intervention, ensuring minimal risk to participants while providing valuable data on the vaccine's efficacy and safety in a high-risk population.

The clinical trial involves the administration of **Prevenar 20**, a pneumococcal polysaccharide conjugate vaccine (20-valent, adsorbed), which is provided as a suspension for injection in a pre-filled syringe. The vaccine is designed to protect against 20 different serotypes of pneumococcal bacteria. The active substances in the vaccine include pneumococcal polysaccharide serotypes 1, 22F, 15B, 5, 3, 11A, 6A, 18C, 10A, 12F, 19A, 33F, 7F, 8, 4, 14, 9V, 6B, 23F, and 19F, each conjugated to the CRM197 carrier protein and adsorbed on aluminium phosphate. The vaccine is administered via **intramuscular injection** with a dosage of 0.5 ml per administration. The maximum treatment period is one day, with a single dose being the total dose administered.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the immunogenicity and safety of the Prevenar 20 vaccine when administered during an acute febrile illness in adults. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to demonstrate that the immune response at one month post-vaccination during an acute febrile illness is non-inferior to the response obtained when the vaccine is administered 15-58 days after the resolution of the illness in unvaccinated patients at high and medium risk for pneumococcal infections.

The efficacy of the 20-valent pneumococcal conjugate vaccine (PCV-20) in the clinical trial will be assessed primarily by evaluating the proportion of immune "good responders" at one month post-vaccination. A "good responder" is defined by achieving a **seroconversion** with a 2-fold increase in vaccine-type (VT) IgG for at least 10 out of 13 tested serotypes, as measured by ELISA, and an immune protective response with ELISA IgG levels greater than 1.3 µg/mL for the same number of serotypes. Alternatively, a 4-fold increase in VT IgG for the same number of serotypes, with ELISA IgG levels less than 1.3 µg/mL, also qualifies as a "good responder." These assessments will be conducted in both arms of the study.

Secondary endpoints include safety assessments, such as the number, type, and severity of adverse events, and the frequency of local and systemic reactions within one month post-vaccination. Additionally, the trial will measure the proportion of immune good responders serotype by serotype, OPA IgG titers, and the frequency of specific PCV-20 IFNg secreting CD4 or CD8 T cells at one month and one year post-vaccination. Other secondary endpoints involve the number of low respiratory tract infections and confirmed S. pneumoniae infections until one year after inclusion, as well as the description of gut microbiome diversity and richness before vaccination. The trial will also analyze fold change kinetics of vaccine-induced gene signatures and serum cytokine levels at baseline and 24 hours post-vaccination, and the proportion of volunteers with circulatory IgA specific to pneumococcus at one month post-vaccination.