Analysing vaccine efficacy evaluated in phase 3 clinical trials carried out during outbreaks.

In this paper we examine several definitions of vaccine efficacy (VE) that we found in the literature, for diseases that express themselves in outbreaks, that is, when the force of infection grows in time, reaches a maximum and then vanishes. The fact that the disease occurs in outbreaks results in several problems that we analyse. We propose a mathematical model that allows the calculation of VE for several scenarios. Vaccine trials usually needs a large number of volunteers that must be enrolled. Ideally, all volunteers should be enrolled in approximately the same time, but this is generally impossible for logistic reasons and they are enrolled in a fashion that can be replaced by a continuous density function (for example, a Gaussian function). The outbreak can also be replaced by a continuous density function, and the use of these density functions simplifies the calculations. Assuming, for example Gaussian functions, one of the problems one can immediately notice is that the peak of the two curves do not occur at the same time. The model allows us to conclude: First, the calculated vaccine efficacy decreases when the force of infection increases; Second, the calculated vaccine efficacy decreases when the gap between the peak in the force of infection and the peak in the enrollment rate increases; Third, different trial protocols can be simulated with this model; different vaccine efficacy definitions can be calculated and in our simulations, all result are approximately the same. The final, and perhaps most important conclusion of our model, is that vaccine efficacy calculated during outbreaks must be carefully examined and the best way we can suggest to overcome this problem is to stratify the enrolled volunteer's in a cohort-by-cohort basis and do the survival analysis for each cohort, or apply the Cox proportional hazards model for each cohort.

Impact after 10-year use of pneumococcal conjugate vaccine in the Brazilian national immunization program: an updated systematic literature review from 2015 to 2020.

In 2010, a 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) was introduced in the Brazilian national immunization program; the 3 + 1 dose schedule was replaced by a 2 + 1 dose schedule in 2016. This systematic review presents the latest published evidence (2015-2020) on the impact after 10-year use of PHiD-CV in Brazil from a total of 29 publications. Overall, the PHiD-CV program had a positive impact on the morbidity and mortality associated with invasive pneumococcal disease (IPD), pneumonia and acute otitis media (AOM) in children <5 years-old. A reduction in the vaccine-type invasive disease was observed in all-ages; suggesting indirect protection unvaccinated older children and adults. The occurrence of non-vaccine type disease was evidenced in some studies. Higher vaccination coverage is required at national and state level for sustained population impact. Given the change in the vaccination schedule and the dynamics of pneumococcal disease epidemiology, continuous surveillance is warranted.GSK Study identifier: HO-18-19438.

A prospective, multicentre, cohort study to assess the incidence of dengue illness in households from selected communities in Brazil (2014-2018).

OBJECTIVES: To estimate the incidence of dengue infection across geographically distinct areas of Brazil. METHODS: This prospective, household-based, cohort study enrolled participants in five areas and followed them up for up to 4 years (2014-2018). Dengue seroprevalence was assessed at each scheduled visit. Suspected dengue cases were identified through enhanced passive and active surveillance. Acute symptomatic dengue infection was confirmed through reverse-transcriptase quantitative polymerase chain reaction in combination with an antigenic assay (non-structural protein 1) and serology. RESULTS: Among 3300 participants enrolled, baseline seroprevalence was 76.2%, although only 23.3% of participants reported a history of dengue. Of 1284 suspected symptomatic dengue cases detected, 50 (3.9%) were laboratory-confirmed. Based on 8166.5 person-years (PY) of follow-up, the incidence of laboratory-confirmed symptomatic infection (primary endpoint) was 6.1 per 1000 PY (95% confidence interval [CI]: 4.5, 8.1). Incidence varied substantially in different years (1.8-7.4 per 1000 PY). The incidence of inapparent primary dengue infection was substantially higher: 41.7 per 1000 PY (95% CI: 31.1, 54.6). CONCLUSIONS: Our findings, highlighting that the incidence of dengue infection is underestimated in Brazil, will inform the design and implementation of future dengue vaccine trials. CLINICAL TRIAL REGISTRATION: NCT01751139.

Epidemiology of pertussis among adolescents, adults, and older adults in selected countries of Latin American: a systematic review.

We aimed to describe the impact of pertussis on adolescents, adults, and older adults over 2007-2018 in selected Latin American countries by reviewing the literature. We searched the Medline, Embase, Scopus, LILACS, Scielo, Google Scholar, CAPES Journals Web-portal, and Cochrane databases for observational epidemiological studies, clinical trials, and systematic reviews of primary studies. Data were extracted and analyzed for all individuals aged ≥10 years. Of 6,891 studies identified only 25 were eligible. Studies were conducted in Brazil (14), Argentina (4), Colombia (4), Mexico (2) and Chile (1). Epidemiological data among target population were limited. No studies clearly assessed the status of asymptomatic or oligosymptomatic B. pertussis carriers in these age groups. Among all pertussis cases identified, the percentage of patients ≥10 years-old ranged between 2.1% and 66.7% depending on country and sample characteristics. The definition of cases, diagnostic methods, and age groups were not consistent across studies.

Meningococcal disease epidemiology in Brazil (2005-2018) and impact of MenC vaccination.

BACKGROUND: Meningococcal disease (MD) presents a substantial public health problem in Brazil. Meningococcal C conjugate (MenC) vaccination was introduced into the routine infant immunization program in 2010, followed by adolescent vaccination in 2017. We evaluated changes in national and regional MD incidence and mortality between 2005 and 2018, serogroup distribution and vaccine coverage. METHODS: Data were obtained from national surveillance systems from 2005 to 2018. Age-stratified incidence and mortality rates were calculated and a descriptive time-series analysis was performed comparing rates in the pre-(2005-2009) and post-vaccination (2011-2018) periods; MD due to specific meningococcal serogroups were analyzed in the pre-(2007-2009) and post-vaccination (2011-2018) periods. RESULTS: From 2005 to 2018, 31,108 MD cases were reported with 6496 deaths; 35% of cases and deaths occurred in children < 5 years. Incidence and mortality rates declined steadily since 2012 in all age-strata, with significantly lower incidence and mortality in the post-vaccine introduction period in children aged < 1-year, 1-4 years, 5-9 years and 10-14 years. A significant decline in MenC disease in children < 5 years was observed following MenC vaccine introduction; infants < 1 year, from 3.30/100,000 (2007-2009) to 1.08/100,000 (2011-2018) and from 1.44/100,000 to 0.42/100,000 in 1-4-year-olds for these periods. Reductions in MenB disease was also observed. MenW remains an important cause of MD with 748 cases reported across 2005-2018. While initial infant vaccination coverage was high (>95% nationwide), this has since declined (to 83% in 2018); adolescent uptake was < 20% in 2017/18). Regional variations in outcomes and vaccine coverage were observed. CONCLUSION: A substantial decline in incidence and mortality rates due to MD was seen following MenC vaccine introduction in Brazil, especially among children < 5 years chiefly driven by reductions in MenC serogroup. While these benefits are considerable, the prevalence of MD due to other serogroups such as MenW and MenB remains a concern. A video summary linked to this article can be found on Figshare: https://doi.org/10.6084/m9.figshare.13379612.v1.

Pertussis epidemiological pattern and disease burden in Brazil: an analysis of national public health surveillance data.

Objective: We described pertussis epidemiological trends in Brazil between 2010 and 2015. We also assessed tetanus, diphtheria and acellular pertussis (Tdap) vaccine coverage among pregnant women from 2014, the year of the introduction of Tdap maternal immunization recommendation in Brazil, to 2016.Methods: Epidemiological data for incidence, prevalence, hospitalization, mortality, and maternal vaccination coverage were calculated based on the Brazilian public surveillance databases.Results: The epidemiological data analysis results showed that the pertussis average incidence rate (IR) was 2.19/100,000 inhabitants for all ages, with a peak in 2014 (4.03/100,000 inhabitants) and highest incidence in <1-year-old children (IR = 175.20/100,000). 97.6% of pertussis deaths (405/415) were in <1-year-old children. Maternal immunization coverage was 9.2% in 2014, 40.4% in 2015, and 33.8% in 2016.Conclusions: Pertussis incidence and pertussis-related deaths increased in Brazil from 2010 to 2014 and decreased in 2015. In the two years, 2015 and 2016 that followed the NIP recommendation, Tdap vaccination coverage of pregnant women was low and varying from region to region. More efforts and national plans would help increase awareness and maternal immunization coverage.

Safety of reduced antigen content diphtheria-tetanus-acellular pertussis vaccine when administered during pregnancy as part of the maternal immunization program in Brazil: a single center, observational, retrospective, cohort study.

Reduced antigen diphtheria-tetanus-acellular pertussis (Tdap) vaccination is included in the maternal immunization program in Brazil since September 2014. We investigated associations between maternal Tdap vaccination and pregnancy-related adverse events (AEs) (gestational diabetes, pregnancy-related hypertension, and pregnancy hemorrhage) and neonatal AEs of interest (preterm birth and small for gestational age). This descriptive, observational, retrospective, single-center study in Brazil (NCT02757950) compared data from medical charts of 1203 pregnant women who received Tdap as part of the maternal immunization program and delivered between May 2015 and February 2017 (exposed cohort) and 1259 unvaccinated women who delivered between September 2012 and August 2014 (unexposed cohort). Index dates were defined as the time of vaccination (27-39 gestational weeks; exposed cohort) or 27 gestational weeks (unexposed cohort). Cumulative incidences were calculated as the number of women with each event between index and delivery dates divided by the total number of women with vaccination date available in the exposed cohort (N = 1199) or the total number of women in the unexposed cohort (N = 1259). Cumulative incidences per 1000 persons were 8.34 versus 17.47 for gestational diabetes, 9.17 versus 24.62 for pregnancy-related hypertension, 3.34 versus 15.09 for pregnancy hemorrhage, 53.38 versus 96.11 for preterm birth, and 57.55 versus 49.25 for small for gestational age in the exposed versus unexposed cohorts. No increased risk of pregnancy-related AEs or neonatal AEs of interest was found following maternal vaccination with Tdap. These results should be interpreted cautiously due to limitations inherent to retrospective observational studies.

A cross-sectional study assessing the pharyngeal carriage of Neisseria meningitidis in subjects aged 1-24 years in the city of Embu das Artes, São Paulo, Brazil.

Meningococcal carriage is a prerequisite for invasive infection. This cross-sectional study assessed the pharyngeal carriage prevalence in healthy subjects aged 1-24 years in Embu das Artes city, São Paulo, Brazil. Pharyngeal swabs were examined for the presence of Neisseria meningitidis. The isolates were tested for different serogroups using agglutination and polymerase chain reaction. A logistic regression model assessed any independent association between Neisseria meningitidis carriage and various risk factors. A total of 87/967 subjects (9%, 95% Confidence Interval (CI): 7.3-11.0) tested positive for N. meningitidis: 6.2% (95% CI: 3.8-9.4) in 1-4 years, 8.5% (95% CI: 5.1-13.0) in 5-9 years, 12.5% (95% CI: 7.8-18.6) in 10-14 years, 12.6% (95% CI: 7.4-19.7) in 15-19 years and 9% (95% CI: 4.9-14.9) in 20-24 years age groups. Highest carriage prevalence was observed in adolescents 10-19 years old. Serogroup C was predominant (18.4%) followed by serogroup B (12.6%). The 15-19 years age group showed a significant association between number of household members and carriers of N. meningitidis. This cross-sectional study is the first in Brazil to evaluate meningococcal carriage prevalence and associated factors in a wide age range.

Etiologies of rash and fever illnesses in Campinas, Brazil.

BACKGROUND: Few population-based studies of infectious etiologies of fever-rash illnesses have been conducted. This study reports on enhanced febrile-rash illness surveillance in Campinas, Brazil, a setting of low measles and rubella virus transmission. METHODS: Cases of febrile-rash illnesses in individuals aged <40 years that occurred during the period 1 May 2003-30 May 2004 were reported. Blood samples were collected for laboratory diagnostic confirmation, which included testing for adenovirus, dengue virus, Epstein-Barr virus (EBV), enterovirus, human herpes virus 6 (HHV6), measles virus, parvovirus-B19, Rickettsia rickettsii, rubella virus, and group A streptococci (GAS) infections. Notification rates were compared with the prestudy period. RESULTS: A total of 1248 cases were notified, of which 519 (42%) had laboratory diagnosis. Of these, HHV-6 (312 cases), EBV (66 cases), parvovirus (30 cases), rubella virus (30 cases), and GAS (30 cases) were the most frequent causes of infection. Only 10 rubella cases met the rubella clinical case definition currently in use. Notification rates were higher during the study than in the prestudy period (181 vs 52.3 cases per 100,000 population aged <40 years). CONCLUSIONS: Stimulating a passive surveillance system enhanced its sensitivity and resulted in additional rubella cases detected. In settings with rubella elimination goals, rubella testing may be considered for all cases of febrile-rash illness, regardless of suspected clinical diagnosis.

[Epidemiologic surveillance of measles and rubella in Campinas (SP), Brazil: the reliability of the data]. / Vigilância epidemiológica do sarampo e da rubéola no Município de Campinas (SP), Brasil: confiabilidade dos dados.

OBJECTIVE: To evaluate and validate the information concerning measles and rubella from the Brazilian National Disease Notification System (BNDNS) (Sistema Nacional de Informação de Agravos de Notificação, or SINAN) for Campinas, a large city in the state of São Paulo, Brazil, using as a reference the data from a control system, the Syndromic Surveillance System for Fever and Exanthem (SSSFE) (Sistema de Vigilância Sindrômica de Febre e Exantema, or VigiFEx), which operated from May 2003 through June 2004. METHOD: In our study we compared: (1) annual data from BNDNS for the years 1999 through 2003 and (2) data from BNDNS and data from SSSFE for the period of June 2003 through May 2004. We analyzed the rate of completion for key fields (record number, date of notification, and city of notification) as well as for name of disease, date of first symptoms, name of patient, birth date and age, sex, city of residence, date of investigation, immunization history, presence of exanthem, date at start of exanthem, presence of fever, suspected cases among pregnant women, signs and symptoms, date of collection of first sample, results with the sample, virus isolation, final classification, criteria for confirmation/exclusion of cases, diagnosis of excluded patients, development of the case, and date of closure. The level of agreement between the recorded cases in the two data banks was also analyzed. RESULTS: From June 2003 through May 2004, 211 suspected cases of measles or rubella were identified in SSSFE and 275 in BNDNS. All the records had complete information concerning the three key fields. The rate of completion was also 100% for patient name, disease, and city of residence. The completion rate was higher than 95% for date of investigation, measles vaccine, measles and rubella vaccine, and rubella vaccine. A lower completion rate was found for other vaccination variables (number of doses and date of last dose) and for exanthem, fever, and date of start of exanthem. The two information systems were not completely consistent, particularly in terms of variables related to epidemiologic background, clinical data, and case closure. The quality of the SSSFE data was higher. CONCLUSIONS: Epidemiologic surveillance, immunization, and laboratory information systems need to undergo routine evaluation to ensure that the data are reliable and can support the planning of public health efforts.