Fouling Behavior during Sterile Filtration of Different Glycoconjugate Serotypes Used in Conjugate Vaccines.

PURPOSE: Sterile filtration can be a particular challenge when processing very large glycoconjugate vaccines. The objective of this study was to examine the sterile filtration performance of a series of glycoconjugate vaccines produced by coupling different polysaccharide serotypes to an immunogenic protein. METHODS: Sterile filtration was performed at constant filtrate flux using 0.22 µm pore size Durapore® polyvinylidene fluoride membranes. Glycoconjugates were characterized by dynamic light scattering, rheological measurements, and nanoparticle tracking analysis (NTA). Confocal microscopy was used to examine glycoconjugate capture profiles within the membrane. Transmembrane pressure data were analyzed using a recently developed fouling model. RESULTS: All glycoconjugates deposited in a narrow band near the entrance of the Durapore® membranes. The rate of fouling varied significantly for the different serotypes, with the fouling parameter correlated with the fraction of glycoconjugates larger than 200 nm in size. CONCLUSIONS: The fouling behavior and sterile filter capacity of the different glycoconjugate serotypes are determined primarily by the presence of large species (>200 nm in size) as determined by nanoparticle tracking analysis. The modified intermediate pore blockage model provides a framework for predicting the sterile filtration performance for these glycoconjugate vaccines.

Saccharide dosage content of meningococcal polysaccharide conjugate vaccines determined using WHO International Standards for serogroup A, C, W, Y and X polysaccharides.

Potency of meningococcal polysaccharide-protein conjugate vaccines relies on the polysaccharide content to prevent meningitis. NIBSC, as the official national control laboratory in UK, analysed ten different mono- and multi-meningococcal conjugate vaccines, using established International Standards for meningococcal serogroups A, C, W, Y and X, by resorcinol or HPAEC-PAD assay. Most saccharide contents were within ±20% of their claimed content for licensure with taking different O-acetylation levels into consideration, with only MenC content in two vaccines below (by 60% and 54%) the labelled value, however, previous study showed different dosage was not necessarily correlated to the immunogenicity of those vaccines. This study demonstrated the use of International Standards to quantify saccharide content in polysaccharide-based vaccines with different percentage of O-acetylation. These International Standards are suitable to serve as either quantitative standard or calibrator of in-house standards, with supplied stability data.

Evaluation of two WHO First International Standards for Vi polysaccharide from Citrobacter freundii and Salmonella enterica subspecies enterica serovar Typhi.

Numerous Vi capsular polysaccharide (Vi PS) conjugate vaccines to protect young children and infants from Typhoid are either licensed or under development. These vaccines are evaluated by laboratory methods to ensure their potency and that quality requirement are met. International Standard (IS) preparations of Vi PS are needed to calibrate and harmonise these assays. Twenty laboratories from 12 countries participated in a collaborative study to evaluate two candidate ISs: Citrobacter freundii Vi PS (NIBSC code 12/244) and Salmonella enterica serovar Typhi Vi PS (16/126). On the basis of returned results and stability profiles, these standards were established by the WHO Expert Committee on Biological Standardization in Oct 2017 as the First WHO IS for C. freundii Vi PS with a content of 1.94 ±â€¯0.12 mg Vi PS per ampoule (expanded uncertainty with coverage factor of k = 2.11 corresponding to a 95% level of confidence) and the First WHO IS for S. Typhi Vi PS with a content of 2.03 ±â€¯0.10 mg Vi PS per ampoule (expanded uncertainty with coverage factor of k = 2.11), as determined by quantitative NMR. The study also showed the ISs are suitable for physicochemical and immuno assays used for the quantitation of the Vi PS component in Vi PS and conjugate vaccines.

Hospitalisation for lower respiratory tract infection in children in the province of Quebec, Canada, before and during the pneumococcal conjugate vaccine era.

Streptococcus pneumoniae is an important cause of community-acquired pneumonia and pneumococcal conjugate vaccines (PCVs) may reduce this burden. This study's goal was to analyse trends in lower respiratory tract infections (LRTI) hospitalisations before and during a routine vaccination programme targeting all newborns with PCV was started in the province of Quebec, Canada in December 2004. The study population included hospital admissions with a main diagnosis of LRTI among 6-59 month-old Quebec residents from April 2000 to December 2014. Trends in proportions and rates were analysed using Cochran-Armitage tests and Poisson regression models. We observed a general downward trend in all LTRI hospitalisations rate: from 11·55/1000 person-years in 2000-2001 to 9·59/1000 in 2013-2014, a 17·0% reduction, which started before the introduction of PCV vaccination. Downward trends in hospitalisation rates were more pronounced for all-cause of pneumonia (minus 17·8%) than for bronchiolitis (minus 15·4%). There was also a decrease in the mean duration of hospital stay. There was little evidence that all-cause pneumonia decreased over the study period due mainly to the introduction of PCVs. Trends may be related to changes in clinical practice. This study casts doubt on the interpretation of ecological analyses of the implementation of PCV vaccination programmes.

Estimating strain-specific and overall efficacy of polyvalent vaccines against recurrent pathogens from a cross-sectional study.

Evaluating vaccine efficacy for protection against colonization with bacterial pathogens is an area of growing interest. Colonization of the nasopharynx is an asymptomatic carrier state responsible for person-to-person transmission. It differs from most clinical outcomes in that it is common, recurrent, and observed only in its prevalent state. To estimate rates of acquisition and clearance of colonization requires repeated active sampling of the same individuals over time, an expensive and invasive undertaking. Motivated by feasibility constraints in efficacy trials with colonization endpoints, investigators have been estimating vaccine efficacy from cross-sectional studies without principled methods. We present two examples of vaccine studies estimating vaccine efficacy from cross-sectional data on nasopharyngeal colonization by Streptococcus pneumoniae (pneumococcus). This study presents a framework for defining and estimating strain-specific and overall vaccine efficacy for susceptibility to acquisition of colonization (VE(acq)) when there is a large number of strains with mutual interactions and recurrent dynamics of colonization. We develop estimators based on one observation of the current status per study subject, evaluate their robustness, and re-analyze the two vaccine trials. Methodologically, the proposed estimators are closely related to case-control studies with prevalent cases, with appropriate consideration of the at-risk time in choosing the controls.

Invasive pneumococcal disease in Australia 2007 and 2008.

Enhanced surveillance for invasive pneumococcal disease (IPD) was conducted in all Australian states and territories in 2007 and 2008 with comprehensive comparative data available since 2002. There were 1,477 cases of IPD notified to the National Notifiable Diseases Surveillance System in Australia in 2007; a notification rate of 7.0 cases per 100,000 population. In 2008 there were 1,628 cases; a notification rate of 7.6 cases per 100,000 population. The overall rate of IPD in Indigenous Australians was almost 6 times the rate in non-Indigenous Australians in 2007 and almost 5 times in 2008. By 2008, the 4th year of a funded universal infant 7-valent pneumococcal conjugate vaccine (7vPCV) program in Australia with a 3+0 schedule, vaccine serotype IPD notification rates in those identified as non-Indigenous decreased in all age groups compared with 2002 levels, most significantly by 96% in children aged less than 5 years. However, rates of disease in non-vaccine serotypes increased by 168% in children aged less than 5 years, including a four-fold increase in the number of cases due to serotype 19A. For the Aboriginal and Torres Strait Islander population, national pre-vaccination data are not available, as the vaccine program was funded for this group from 2001. From 2002 to 2008, the proportion of disease due to 7vPCV serotypes in children aged less than 5 years decreased by 77%, while disease due to non-7vPCV serotypes increased by 76%. In Indigenous adults (≥50 years), rates of 23vPPV serotypes increased by 92%. There were 120 deaths attributed to IPD in 2007 and 113 in 2008, although it should be noted that deaths may be under-reported. The number of invasive pneumococcal isolates with reduced penicillin susceptibility remains low and reduced susceptibility to third-generation cephalosporins is rare.

Defining Polysaccharide-Specific Antibody Targets against Vibrio cholerae O139 in Humans following O139 Cholera and following Vaccination with a Commercial Bivalent Oral Cholera Vaccine, and Evaluation of Conjugate Vaccines Targeting O139.

Cholera caused by Vibrio cholerae O139 could reemerge, and proactive development of an effective O139 vaccine would be prudent. To define immunoreactive and potentially immunogenic carbohydrate targets of Vibrio cholerae O139, we assessed immunoreactivities of various O-specific polysaccharide (OSP)-related saccharides with plasma from humans hospitalized with cholera caused by O139, comparing responses to those induced in recipients of a commercial oral whole-cell killed bivalent (O1 and O139) cholera vaccine (WC-O1/O139). We also assessed conjugate vaccines containing selected subsets of these saccharides for their ability to induce protective immunity using a mouse model of cholera. We found that patients with wild-type O139 cholera develop IgM, IgA, and IgG immune responses against O139 OSP and many of its fragments, but we were able to detect only a moderate IgM response to purified O139 OSP-core, and none to its fragments, in immunologically naive recipients of WC-O1/O139. We found that immunoreactivity of O139-specific polysaccharides with antibodies elicited by wild-type infection markedly increase when saccharides contain colitose and phosphate residues, that a synthetic terminal tetrasaccharide fragment of OSP is more immunoreactive and protectively immunogenic than complete OSP, that native OSP-core is a better protective immunogen than the synthetic OSP lacking core, and that functional vibriocidal activity of antibodies predicts in vivo protection in our model but depends on capsule thickness. Our results suggest that O139 OSP-specific responses are not prominent following vaccination with a currently available oral cholera vaccine in immunologically naive humans and that vaccines targeting V. cholerae O139 should be based on native OSP-core or terminal tetrasaccharide. IMPORTANCE Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae serogroup O1 or O139. Protection against cholera is serogroup specific, and serogroup specificity is defined by O-specific polysaccharide (OSP). Little is known about immunity to O139 OSP. In this study, we used synthetic fragments of the O139 OSP to define immune responses to OSP in humans recovering from cholera caused by V. cholerae O139, compared these responses to those induced by the available O139 vaccine, and evaluated O139 fragments in next-generation conjugate vaccines. We found that the terminal tetrasaccharide of O139 is a primary immune target but that the currently available bivalent cholera vaccine poorly induces an anti-O139 OSP response in immunologically naive individuals.

Safety assessment of recalled Haemophilus influenzae type b (Hib) conjugate vaccines--United States, 2007-2008.

PURPOSE: On 13 December 2007, Merck & Co., Inc. voluntarily recalled 1.2 million doses of Haemophilus influenzae type b (Hib) vaccines that had been distributed since April 2007 for concerns regarding potential Bacillus cereus contamination. Enhanced postrecall surveillance was conducted to detect vaccine-associated B. cereus infections. METHODS: We reviewed reports involving recalled Hib vaccines received by the Vaccine Adverse Event Reporting System (VAERS) during 1 April 2007-29 February 2008. For each reported death, autopsy review sought evidence of B. cereus infections. For each specified outcome, the proportional reporting ratios (PRRs) were calculated to compare the recalled Hib vaccines with the manufacturer's nonrecalled Hib vaccines in the VAERS databases. On 20 December 2007, we used the Epidemic Information Exchange (Epi-X) to solicit nongastrointestinal vaccine-associated B. cereus infections, and requested B. cereus isolates for genotyping to compare with the manufacturing facility isolate. RESULTS: VAERS received 75 reports involving recalled Hib vaccines; none described a confirmed B. cereus infection. Comparative analyses did not reveal disproportionate reporting of specified outcomes for recalled Hib vaccines. The Epi-X posting triggered one report of vaccine-associated B. cereus bacteremia from a child who received a nonrecalled Hib vaccine manufactured by Merck; the genotypes of isolates from the patient and the manufacturing facility differed. CONCLUSIONS: No evidence of vaccine-associated B. cereus infection had been found in recipients of recalled Hib vaccines. Conducting laboratory surveillance through Epi-X was feasible and may enhance public health response capacities for future vaccine safety emergencies.

Meningococcal and pneumococcal carriage in Hajj pilgrims: findings of a randomized controlled trial.

BACKGROUND: Intense congestion during the Hajj pilgrimage amplifies the risk of meningococcal carriage and disease, and there have been many meningococcal outbreaks reported amongst pilgrims. Thus, a strict vaccination policy is enforced by the host country and either polysaccharide or conjugate quadrivalent meningococcal vaccines are mandatory. However, unlike conjugate vaccines, the polysaccharide vaccine is not thought to reduce pharyngeal carriage of meningococci. METHODS: A single-blinded, randomized, controlled trial amongst pilgrims from Saudi Arabia and Australia during the Hajj seasons of 2016-2017 was conducted to compare MenACWY-Conjugate vaccine with MenACWY-Polysaccharide vaccine, to determine if the conjugate vaccine is more effective in reducing asymptomatic carriage of meningococci, and whether the effect may be long-standing. Oropharyngeal swabs were obtained pre-, immediately post- and 6-11 months following completion of Hajj and tested for the presence of meningococci. RESULTS: Amongst 2000 individuals approached, only 1146 participants aged 18-91 (mean 37.6) years agreed to participate and were randomized to receive either the polysaccharide (n = 561) or the conjugate (n = 561) vaccine, 60.8% were male, and 93.5% were from Saudi Arabia. Amongst oropharyngeal swabs obtained before Hajj, only two (0.2%) tested positive for Neisseria meningitidis. Similarly, meningococci were identified in only one sample at each of the post-Hajj and late follow-up visits. None of the carriage isolates were amongst the serogroups covered by the vaccines. A post hoc analysis of the third swabs revealed that 22.4% of all participants (50/223) were positive for Streptococcus pneumoniae nucleic acid. CONCLUSION: The low overall carriage rate of meningococci found amongst Hajj pilgrims in 2016 and 2017 demonstrates a successful vaccination policy, but neither supports nor refutes the superiority of meningococcal conjugate ACWY vaccine over the polysaccharide vaccine against carriage. Although an association could not be established in this study, molecular epidemiology would help to establish the role of Hajj in facilitating transmission of pneumococci and inform vaccination policy.

Dynamic transmission models and economic evaluations of pneumococcal conjugate vaccines: a quality appraisal and limitations.

BACKGROUND: Of over 90 serotypes of Streptococcus pneumoniae, only seven were included in the first pneumococcal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. AIM: The aim of this review was to examine epidemiological and economic models and their assumptions for their potential contributions to future research and immunisation policy. SOURCES: Pubmed, Scopus, Ovid, ISI Web of Knowledge, Centre of Reviews and Dissemination (CRD) databases were searched. CONTENT: Twenty-three dynamic transmission models and 21 economic models were retrieved and reviewed. Published models employed various templates, revealing several key uncertainties regarding the biology and epidemiology of pneumococcal infection. While models suggested that PCVs will reduce the burden of disease, the extent to which they are predicted to do so depended on various assumptions regarding features of pneumococcal infection and epidemiology that governed PCV cost-effectiveness as well. Such features include the duration of protection and competitive interactions between serotypes, which are unclear at present, but which directly relate to herd immunity and serotype replacement. IMPLICATIONS: Economic evaluations are not typically based on transmission dynamic models and hence omit indirect herd immunity effects. The two tools could be used in conjunction to inform decision-makers on vaccine implementation, but so far there have been few attempts to build economic evaluations on transmission dynamic models, and none in this field. Future directions for research could include studies to evaluate key parameters for the models involving herd immunity, serotype competition and the natural history of infection.

Evaluation of sequential multiplex PCR for direct detection of multiple serotypes of Streptococcus pneumoniae from nasopharyngeal secretions.

Sequential multiplex PCR was evaluated for detection of multiple Streptococcus pneumoniae serotypes directly from nasopharyngeal secretions. A total of 279 nasopharyngeal swab samples were tested blindly. When limited to the 29 serotypes identifiable by the molecular method, the mean number of serotypes identified by the conventional latex/Quellung method was 0.85, which was significantly lower than that by the molecular method (P <0.0001). The multiplex PCR method identified significantly more serotypes than the latex/Quellung method if limited to the 29 serotypes (P=0.001 and P=0.014, respectively).

Licensure of a Haemophilus influenzae type b (Hib) vaccine (Hiberix) and updated recommendations for use of Hib vaccine.

On August 19, 2009, the Food and Drug Administration (FDA) licensed Hiberix (GlaxoSmithKline Biologicals, Rixensart, Belgium), a Haemophilus influenzae type b (Hib) conjugate vaccine composed of H. influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]) conjugated to inactivated tetanus toxoid (PRP-T). Hiberix is licensed for use as the booster (final) dose of the Hib vaccine series for children aged 15 months through 4 years (before the 5th birthday) who have received previously the primary series of Hib vaccination (consisting of 2 or 3 doses, depending on the formulation). The Advisory Committee on Immunization Practices (ACIP) recommends Hib booster vaccination for children at ages 12 through 15 months; however, because of the recent shortage of Hib vaccines, many children have deferred the booster dose and therefore require catch-up vaccination. This report summarizes the indications for Hiberix use and provides guidance on Hib booster dose administration based on increasing vaccine supplies. Vaccination recommendations in this report update the previous advisory on Hib booster administration (June 26, 2009), which advised that children with deferred booster doses receive it at the next regularly scheduled visit. Vaccination providers are now recommended to begin recall of children in need of the booster dose when feasible and monovalent Hib vaccine supply in the office is adequate.

Pneumococcal conjugate vaccine update.

ACIP no longer recommends routine use of PCV13 in immunocompetent adults ≥ 65 years. Three simple statements summarize guidance on intervals to follow when administering both PCV13 and PPSV23.

A systematic literature review and network meta-analysis feasibility study to assess the comparative efficacy and comparative effectiveness of pneumococcal conjugate vaccines.

Background: No head-to-head studies are currently available comparing pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) with 13-valent pneumococcal conjugate vaccine (PCV-13). This study explored the feasibility of using network meta-analysis (NMA) to conduct an indirect comparison of the relative efficacy or effectiveness of the two vaccines.Methods: A systematic literature search was conducted for published randomized controlled trials (RCTs) and non-RCT studies reporting data on vaccine efficacy or effectiveness against invasive pneumococcal disease in children aged <5 years receiving 7-valent pneumococcal conjugate vaccine (PCV-7), PHiD-CV or PCV-13. Study quality was evaluated using published scales. NMA feasibility was assessed by considering whether a connected network could be constructed by examining published studies for differences in study or patient characteristics that could act as potential treatment effect modifiers or confounding variables.Results: A total of 26 publications were included; 2 RCTs (4 publications), 7 indirect cohort studies, and 14 case-control studies (15 publications). Study quality was generally good. The RCTs could not be connected in a network as there was no common comparator. The studies differed considerably in design, dose number, administration schedules, and subgroups analyzed. Reporting of exposure status and subject characteristics was inconsistent.Conclusion: NMA to compare the relative efficacy or effectiveness of PHiD-CV and PCV-13 is not feasible on the current evidence base, due to the absence of a connected network across the two RCTs and major heterogeneity between studies. NMA may be possible in future if sufficient RCTs become available to construct a connected network.

From individual to herd protection with pneumococcal vaccines: the contribution of the Cuban pneumococcal conjugate vaccine implementation strategy.

A new pneumococcal conjugate vaccine is currently undergoing advanced clinical evaluation prior to its planned introduction in Cuba. The implementation of the pneumococcal vaccination strategy has been designed with consideration of the need to maximize both its direct and indirect effects. A novel approach is suggested, which addresses preschool children as the first-line target group to generate herd immunity in infants and to have an impact on transmission at the community level. The clinical evaluation pipeline is described herein, including evaluations of effectiveness, cost-effectiveness, and impact. The scientific contribution of the Cuban strategy could support a paradigm shift from individual protection to a population effect based on a rigorous body of scientific evidence.

Lot-to-lot Consistency, Safety, Tolerability and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants.

BACKGROUND: This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). METHODS: Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. RESULTS: The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. CONCLUSIONS: HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.

Pneumococcal conjugate vaccination in children with recurrent acute otitis media: a therapeutic alternative?

BACKGROUND: Based on two clinical trials in healthy infants the American Academy of Pediatrics (AAP) advices immunization with a 7-valent pneumococcal conjugate vaccine in children with recurrent acute otitis media (AOM). OBJECTIVE: To study the efficacy of a 7-valent pneumococcal conjugate vaccine on acute otitis media recurrences, its immunogenicity and impact on nasopharyngeal Streptococcus pneumoniae carriage in children with a history of frequent acute otitis media. METHODS: In this double-blind, randomized study, 74 Belgian children, aged 1-7 years, with at least 2 clinically diagnosed episodes of acute otitis media in the previous year were enrolled. Children were immunized with either a 7-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide booster or a control hepatitis A vaccine. Total follow-up was 26 months. RESULTS: Despite adequate serum IgG responses to all conjugate vaccine pneumococcal serotypes, no reduction of acute otitis media episodes was observed in the pneumococcal vaccine group as compared to the control group (rate ratio: 1.16; 95% CI: 0.69-1.96). Overall nasopharyngeal pneumococcal carriage remained stable. However, a transient shift from conjugate vaccine related S. pneumoniae serogroups to non-vaccine related serogroups was noted following conjugate vaccination. CONCLUSION: Clinically no protective effect of pneumococcal conjugate vaccination on acute otitis media recurrences was found in children with a history of frequent AOM.

Impact of pneumococcal conjugate vaccine on the prevention of invasive pneumococcal diseases.

OBJECTIVES: To evaluate the impact of heptavalent pneumococcal conjugate vaccine in invasive pneumococcal diseases in the United States, and to analyze the potential impact of this vaccine in Brazil. SOURCES OF DATA: MEDLINE, LILACS, Cochrane Database Reviews, as well as the websites of the Centers for Disease Control and Prevention (CDC), Brazilian Ministry of Health and Centro de Vigilância Epidemiológica do Estado de São Paulo from January 2000 to January 2006. Articles retrieved with the keywords Streptococcus pneumoniae, pneumococcal diseases, conjugate vaccine, antimicrobial resistance and meningitis were reviewed. SUMMARY OF THE FINDINGS: The introduction of heptavalent pneumococcal conjugate vaccine caused a dramatic reduction in the incidence of invasive pneumococcal diseases in American children, reduced antibiotic use and the number of medical visits due to otitis media and pneumonia by children. The incidence of invasive pneumococcal diseases caused by resistant strains declined in immunized children, adults and elderly individuals. In Brazil, the mortality rate of pneumococcal meningitis is very high and the resistance to antibiotics has increased over the last 5 years. CONCLUSIONS: Heptavalent pneumococcal conjugate vaccine can benefit not only children, but the entire community and should be included in the Brazilian routine immunization schedule.