Effectiveness, Immunogenicity and Safety of the Second Booster Dose of the Vaccine Against COVID-19 in the Elderly

Study Overview
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Brief Summary
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The objective of this observational case-crossover study is to evaluate the effectiveness, safety and immunogenicity of the second booster dose in the elderly. There are an estimated 490,000 eligible individuals aged 60 and over statewide for the effectiveness study. Two hundred and forty participants will be invited to participate in biological sample for the immunogenicity study. This sub-sample will be compared with 240 biorepository samples from a cohort of immunosuppressed patients with autoimmune diseases who received the fourth dose, in a study conducted by the same team of researchers. The main effectiveness outcome will be the number of hospitalizations; and secondary outcomes will be deaths, number of reported cases, number of cases confirmed by RT-PCR. The safety assessment will be carried out by monitoring adverse events. The cellular and humoral immune response will be evaluated by viral neutralization assay (search for neutralizing antibodies), serological assay by chemiluminescence, determination of specific IgM and IgG profile, dosage of soluble systemic factors (chemokines, cytokines and growth factors), stimulation in vitro antigen-specific peripheral blood mononuclear cells and investigation of memory T and B lymphocytes and intracytoplasmic cytokines. The study hypothesis is that elderly people who received the second booster dose have a lower incidence rate of hospitalizations and death than those who received the primary regimen (two doses or one of Janssen) or a booster dose, and that the immune response humoral and cellular function of the elderly is similar to those who are immunosuppressed.

Detailed Description
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Faced with the new scenario of high transmission of the Ômicron variant of SARS-COV-2, in which the elderly over 60 years and immunosuppressed even vaccinated with three doses have become a population vulnerable to a greater probability of serious illness by Covid-19, demanding an increase in risk of hospitalization and deaths, the application of the fourth dose (second booster dose) has become an alternative to increase protection for these individuals. The general objective of this study is to evaluate the effectiveness, safety and immunogenicity of the second booster dose in the elderly. This is an observational, case-crossover study, based on databases with notification and vaccination records and a cohort study for the analysis of immunogenicity. Elderly people of both sexes aged 60 years or older, residents of Espírito Santo, will be included. There are an estimated 490,000 eligible individuals aged 60 and over statewide for the effectiveness study. Two hundred and forty participants, with quotas distributed by sex (50% male and 50% female) and age group, will be invited to participate in biological sample collection on the day of application of the second booster dose (T1) , 28 days after the second booster dose (T2), at the follow-up visit after 3 months (T3), 150 days (T4) and 180 days (T5), for follow-up of vaccine response and follow-up of duration of immunity, in a health unit in Cariacica-ES. This sub-sample will be compared with 240 biorepository samples from a cohort of immunosuppressed patients with autoimmune diseases who received the fourth dose, in a study conducted by the same team of researchers. The main effectiveness outcome will be the number of hospitalizations, weighted by protection time, 90 days after complete immunization (14th day after second booster dose); and secondary outcomes will be deaths, number of reported cases, number of cases confirmed by RT-PCR. The safety assessment will be carried out by monitoring adverse events. The cellular and humoral immune response will be evaluated by viral neutralization assay (search for neutralizing antibodies), serological assay by chemiluminescence, determination of specific IgM and IgG profile, dosage of soluble systemic factors (chemokines, cytokines and growth factors), stimulation in vitro antigen-specific peripheral blood mononuclear cells and investigation of memory T and B lymphocytes and intracytoplasmic cytokines. The study hypothesis is that elderly people who received the second booster dose have a lower incidence rate of hospitalizations and death than those who received the primary regimen (two doses or one of Janssen) or a booster dose, and that the immune response humoral and cellular function of the elderly is similar to those who are immunosuppressed.

Official Title
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Effectiveness, Immunogenicity and Safety of the Second Booster Dose (Fourth Dose) of the Vaccine Against COVID-19 in the Elderly: Study Reforça Mais (Plus Booster)

Conditions
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COVID-19, Vaccine Adverse Reaction, Vaccine-Preventable Diseases

Intervention / Treatment
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* Biological: ChAdOx1 nCoV-19 or Comirnaty or Janssen COVID-19 Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age equal to or greater than 60 years Residents of Espírito Santo, Brazil Exclusion Criteria: Being under active treatment (chemotherapy and/or radiotherapy) for the treatment of any type of neoplasm Being admitted to an institutionalization establishment for the elderly (hospitals, nursing homes, shelters or similar). Patients with mental illness with inability to understand the consent form

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Effectiveness group<br>There are an estimated 490,000 eligible individuals aged 60 and over statewide for the effectiveness study. | Biological: ChAdOx1 nCoV-19 or Comirnaty or Janssen COVID-19 Vaccine<br>* In a Technical Note, the State of Espírito Santo decided to recommend the application of the fourth dose with vaccines using messenger RNA (mRNA) technology or viral vector vaccine, for all people aged 60 years or older, with an interval of 90 days from of the third dose, considering that, while there is no availability of vaccines adapted to the new variants, boosters with available vaccines are still the most appropriate ways to prevent hospitalization and deaths.<br>|
| Elderly group - Immunogenicity<br>240 participants from the Effectiveness group, with quotas distributed by sex (50% male and 50% female) and age group, will be invited to participate in biological sample collection for the immunogenicity study. | Biological: ChAdOx1 nCoV-19 or Comirnaty or Janssen COVID-19 Vaccine<br>* In a Technical Note, the State of Espírito Santo decided to recommend the application of the fourth dose with vaccines using messenger RNA (mRNA) technology or viral vector vaccine, for all people aged 60 years or older, with an interval of 90 days from of the third dose, considering that, while there is no availability of vaccines adapted to the new variants, boosters with available vaccines are still the most appropriate ways to prevent hospitalization and deaths.<br>|
| Immunosupressed group<br>240 biorepository samples from a cohort of immunosuppressed patients with autoimmune diseases who received the fourth dose, in a study conducted by the same team of researchers. | Biological: ChAdOx1 nCoV-19 or Comirnaty or Janssen COVID-19 Vaccine<br>* In a Technical Note, the State of Espírito Santo decided to recommend the application of the fourth dose with vaccines using messenger RNA (mRNA) technology or viral vector vaccine, for all people aged 60 years or older, with an interval of 90 days from of the third dose, considering that, while there is no availability of vaccines adapted to the new variants, boosters with available vaccines are still the most appropriate ways to prevent hospitalization and deaths.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of hospital admissions | number of hospital admissions for covid-19 recorded in the e-SUS notifica | Change from baseline at 6 months | 
| Number of adverse events | Surveillance of adverse post-vaccine events (PVAE) and adverse events of special interest (EAIE) recorded in the e-SUS notifica | Change from baseline at 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of deaths | Number of deaths with specific ICD for covid-19 recorded in the e-SUS notifica | Change from baseline at 6 months | 
| number of Covid-19 cases | number of Covid-19 cases confirmed by RT-PCR recorded in the e-SUS notifica | Change from baseline at 6 monhts | 
| Viral neutralization assay | Neutralizing antibody titers will be expressed by the ability of antibodies to neutralize up to 50% the number of plaques (PRNT50). Title > 1:50 will be considered positive. | Change from baseline at 1, 3, 5 and 6 months | 
| Serological assay | Serological test by chemiluminescence for qualitative and quantitative determination of specific IgG antibodies against the nucleocapsid protein of SARS-Cov-2. Results are expressed in U/mL and data interpretation will be done as follows: <0.8 U/mL = non-reactive sample; ≥0.8 U/mL = reactive sample. | Change from baseline at 1, 3, 5 and 6 months | 
| Soluble systemic factors | Dosage of soluble systemic factors (chemokines, cytokines and growth factors). Results will be expressed in pg/ml. | Change from baseline at 1, 3, 5 and 6 months | 
| Lymphocyte investigation | Investigation of memory T and B lymphocytes. The results will be expressed in percentage positive frequency for a specific cell phenotype. | Change from baseline at 1, 3, 5 and 6 months | 
| Cytokine investigation | Investigation of intracytoplasmic cytokines. The results will be expressed in percentage positive frequency for a specific cell phenotype. | Change from baseline at 1, 3, 5 and 6 months |