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

Open AccessPublished:April 27, 2017DOI:https://doi.org/10.1016/j.ijid.2017.03.011

      Summary

      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.

      Introduction

      Pneumococcal infection is the leading cause of death at the extreme ages of life (
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      ). The severe forms of pneumococcal disease remain a leading cause of vaccine-preventable disease in young children less than 5 years of age (
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      ). The asymptomatic nasopharyngeal carriage of pneumococci is highly prevalent among young children and is often the first in a sequence of events that leads to disease (
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      ).
      Pneumococcal conjugate vaccines (PCVs) are available in many parts of the world and are highly effective in preventing invasive disease in infants and young children, with favorable safety and immunogenicity profiles. Much of the evidence regarding the impact of PCVs has focused on infants as the target population. It implies the early introduction of pneumococcal vaccination (in the first 6 months of life) to prevent nasopharyngeal colonization and invasive pneumococcal disease (IPD) (
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      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ).
      The feasibility of introducing PCVs into childhood immunization programs has grown, and there is expert consensus about the need to better understand the number and timing of doses to maximize both the direct and indirect effects (
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      ).
      The cost-effectiveness of pneumococcal vaccines has been evaluated globally, mostly in regard to the strategy centered on targeting children less than 1 year of age. Evaluations performed in low- and middle-income countries have generally supported the efficiency of the 10- and 13-valent vaccines versus the 7-valent vaccine or non-immunization (
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      ,
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      ,
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      ,
      • Peña Kieninger M.
      • Giménez Caballero E.
      • Arbo Sosa A.
      • Torres Amarilla C.
      • Jáuregui B.
      • Bess Janusz C.
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      ,
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      • Canelo-Aybar C.
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      • Bess Janusz C.
      • Jaúregui B.
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      ,
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      • Rayanakorn A.
      • Bin-Chia Wu D.
      • Chaiyakunapruk N.
      Cost Effectiveness of Pneumococcal Vaccination in Children in Low- and Middle-Income Countries: A Systematic Review.
      ). However, cost-effectiveness studies in regard to children living in lower income countries are limited (
      • Saokaew S.
      • Rayanakorn A.
      • Bin-Chia Wu D.
      • Chaiyakunapruk N.
      Cost Effectiveness of Pneumococcal Vaccination in Children in Low- and Middle-Income Countries: A Systematic Review.
      ). One possible factor that could explain this apparent discrepancy is the high price of vaccines and the consequent out-of-pocket expenses or effects on public budgets. From the early 2000s to the present, it has been found that the price of the vaccine is one of the determinants of the feasibility of vaccination programs in infants (
      • Constenla D.O.
      Economic impact of pneumococcal conjugate vaccination in Brazil, Chile, and Uruguay.
      ,
      • Atienza Merino G.
      Evaluación económica de un programa de vacunación frente al neumococo en población pediátrica. Santiago de Compostela: Consellería de Sanidade, Axencia de Avaliación de Tecnoloxías Sanitarias de Galicia, avalia-t.
      ,
      • Beutels P.
      • Blommaert A.
      • Hanquet G.
      • Bilcke J.
      • Thiry N.
      • Sabbe M.
      • et al.
      Cost-effectiveness of 10- and 13-valent pneumococcal conjugate vaccines in childhood. Health Technology Assessment (HTA).
      ,
      • Mo X.
      • Gai Tobe R.
      • Liu X.
      • Mori R.
      Cost-effectiveness and Health Benefits of Pediatric 23-valent Pneumococcal Polysaccharide Vaccine, 7-valent Pneumococcal Conjugate Vaccine and Forecasting 13-valent Pneumococcal Conjugate Vaccine in China.
      ).
      Given this reality, some countries, such as those in Eastern Europe (
      • Castiglia P.
      Recommendations for Pneumococcal Immunization Outside Routine Childhood Immunization Programs in Western Europe.
      ), have chosen to adopt a vaccination strategy that focuses on programs outside of routine childhood immunization, mainly aimed at particular risk groups. Others have opted for innovative approaches to financing, such as advanced market commitment (AMC) projects in which the companies that benefit are obliged to provide the vaccine for an extended period at a reduced price (
      • Vujicic M.
      • Weber S.E.
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      • Atun R.
      • Kumar R.
      An analysis of GAVI, the Global Fund and World Bank support for human resources for health in developing countries.
      ,
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      ).
      Hence, economic aspects continue to form the basis of health policies regarding the introduction of pneumococcal vaccination. However, it remains necessary to investigate novel approaches to immunization strategies that go beyond the cost-effectiveness analyses and that integrate vaccination effectiveness, efficiency, and economic sustainability at the population level.
      If a vaccination strategy could be developed based on lower prices, fewer doses, and at least the same effectiveness, this would represent a sustainable proposal particularly for low-income countries and families. This should not be impossible to achieve, and this issue could perhaps be resolved adressing othertarget population as part of the vaccination strategy. There are still unanswered questions that could help with this. For instance, could the vaccination of toddlers stop transmission of vaccine serotypes at the community level, providing a herd effect in infants, even if they are not vaccinated? What coverage will be necessary to achieve herd protection in infants? Is the available scientific evidence sufficient to support this hypothesis? (
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      • Virgilio F.
      • Giglio N.
      • Gentile A.
      • et al.
      Cost-effectiveness analysis of the 10- and 13-valent pneumococcal conjugate vaccines in Argentina.
      ,
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      • Zell E.R.
      • Bronsdon M.
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      • Reid R.
      • et al.
      Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial.
      ,
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      • Reinert R.R.
      Burden of invasive pneumococcal disease and serotype distribution among Streptococcus pneumoniae isolates in young children in Europe: impact of the 7-valent pneumococcal conjugate vaccine and considerations for future conjugate vaccines.
      )
      Previously published studies (
      • Pilishvili T.
      • Lexau C.
      • Farley M.M.
      • Hadler J.
      • Harrison L.H.
      • Bennett N.M.
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ,
      • Loo J.D.
      • Conklin L.
      • Fleming-Dutra K.E.
      • Knoll M.D.
      • Park D.E.
      • Kirk J.
      • et al.
      Systematic review of the indirect effect of pneumococcal conjugate vaccine dosing schedules on pneumococcal disease and colonization.
      ,
      • Bonner K.
      • Welch E.
      • Elder K.
      • Cohn J.
      Impact of Pneumococcal Conjugate Vaccine Administration in Pediatric Older Age Groups in Low and Middle Income Countries: A Systematic Review.
      ) have explored the impact of infant PCVs immunization on unvaccinated older children and adults, because the primary target has always been infants. Many of these studies took place over relatively short periods of time and comprised small and/or sub-studies of clinical trials. The primary immunization of children before infant immunization has been limited.
      Reducing the nasopharyngeal colonization burden among young children less than 5 years old could have an important impact on disease transmission and the reduction in carriage of vaccine serotype strains (
      • O’Brien K.L.
      • Dagan R.
      The potential indirect effect of conjugate pneumococcal vaccines.
      ,
      • Constenla D.O.
      Economic impact of pneumococcal conjugate vaccination in Brazil, Chile, and Uruguay.
      ,
      • Atienza Merino G.
      Evaluación económica de un programa de vacunación frente al neumococo en población pediátrica. Santiago de Compostela: Consellería de Sanidade, Axencia de Avaliación de Tecnoloxías Sanitarias de Galicia, avalia-t.
      ,
      • Beutels P.
      • Blommaert A.
      • Hanquet G.
      • Bilcke J.
      • Thiry N.
      • Sabbe M.
      • et al.
      Cost-effectiveness of 10- and 13-valent pneumococcal conjugate vaccines in childhood. Health Technology Assessment (HTA).
      ,
      • Mo X.
      • Gai Tobe R.
      • Liu X.
      • Mori R.
      Cost-effectiveness and Health Benefits of Pediatric 23-valent Pneumococcal Polysaccharide Vaccine, 7-valent Pneumococcal Conjugate Vaccine and Forecasting 13-valent Pneumococcal Conjugate Vaccine in China.
      ), as they probably play the most important role in sustaining the transmission of pneumococcal infections within the community (
      • Bogaert D.
      • de Groot R.
      • Hermans P.
      Streptococcus pneumoniae colonisation: the key to pneumococcal disease.
      ,
      • Simell B.
      • Auranen K.
      • Kayhty H.
      • Goldblatt D.
      • Dagan R.
      • O’Brien K.L.
      • et al.
      The fundamental link between pneumococcal carriage and disease.
      ). The presence of children in the household has a marked effect on the pneumococcal carriage rate in adults (18–29% nasopharyngeal carriage in households with children less than 6 years of age vs. 6% in households without children) (
      • Levine O.S.
      • Cutts F.T.
      Pneumococcal vaccination and public health.
      ). In addition, daycare attendance is considered a significant risk factor for IPD (
      • Johnson H.L.
      • Deloria-Knoll M.
      • Levine O.S.
      • Stoszek S.K.
      • Hance L.F.
      • Reithinger R.
      • et al.
      Systematic evaluation of serotypes causing invasive pneumococcal disease among children under five: the pneumococcal global serotype project.
      ,
      • Takala A.K.
      • Jero J.
      • Kela E.
      • Rönnberg P.-R.
      • Koskenniemi E.
      • Eskola J.
      Risk factors for primary invasive pneumococcal disease among children in Finland.
      ). Also, living with a sibling younger than 5 years of age (odds ratio 2.51, 95% confidence interval 1.82–3.48) and daycare attendance (odds ratio 2.36, 95% confidence interval 1.26–4.33) have been found to be determinants of nasopharyngeal carriage in Cuba (
      • Toledo M.E.
      • Casanova M.F.
      • Linares-Pérez N.
      • García-Rivera D.
      • Toraño Peraza G.
      • Barcos Pina I.
      • et al.
      Prevalence of Pneumococcal Nasopharyngeal Carriage Among Children 2-18 Months of Age: Baseline Study Pre Introduction of Pneumococcal Vaccination in Cuba.
      ).
      Published data suggest that vaccine coverage of around two-thirds of children younger than 5 years is sufficient to induce herd protection at the population level (
      • Adams W.G.
      • Deaver K.A.
      • Cochi S.L.
      • Plikaytis B.D.
      • Zell E.R.
      • Broome C.V.
      • et al.
      Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era.
      ,
      • Miller E.
      • Andrews N.J.
      • Waight P.A.
      • Slack M.P.
      • George R.C.
      Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study.
      ,
      • Maiden M.C.
      • Ibarz-Pavón A.B.
      • Urwin R.
      • Gray S.J.
      • Andrews N.J.
      • Clarke S.C.
      • et al.
      Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity.
      ,
      • Trotter C.L.
      • Ramsay M.E.
      Vaccination against meningococcal disease in Europe: review and recommendations for the use of conjugate vaccines.
      ,
      • O'Brien K.L.
      • Millar E.V.
      • Zell E.R.
      • Bronsdon M.
      • Weatherholtz R.
      • Reid R.
      • et al.
      Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial.
      ).
      Pneumococcal vaccination has not yet been introduced in Cuba. The major epidemiological burden of IPD concerns children less than 5 years old (
      • Toraño G.
      • Pías L.
      • Capote M.
      • Rodríguez M.
      • Dickinson F.
      • Varcárcel M.
      Serotipos y resistencia antimicrobiana de aislamientos meníngeos de Streptococcus pneumoniae. Cuba, 2007-2012.
      ,
      • Dickinson Meneses Felix R.O.M.
      • Toraño Peraza Gilda
      Pneumococcal meningitis in Cuban children and adolescents: A fifteen years follow up.
      ), and the prevalence rate of nasopharyngeal colonization is more than 20% in infants ≥2 months of age (
      • Toledo M.E.
      • Casanova M.F.
      • Linares-Pérez N.
      • García-Rivera D.
      • Toraño Peraza G.
      • Barcos Pina I.
      • et al.
      Prevalence of Pneumococcal Nasopharyngeal Carriage Among Children 2-18 Months of Age: Baseline Study Pre Introduction of Pneumococcal Vaccination in Cuba.
      ).
      A new Cuban heptavalent vaccine candidate (PCV7-T) is currently undergoing clinical evaluation (
      • Dotres C.P.
      • Puga R.
      • Ricardo Y.
      • Brono C.R.
      • Paredes B.
      • Echemendía V.
      • et al.
      Safety and preliminary immunogenicity of Cuban pneumococcal conjugate vaccine candidate in healthy children: A randomized phase I clinical trial.
      ,
      • González N.
      • Paredes B.
      • Pérez S.
      • Mirabal M.
      • Rivero I.
      • González C.
      • et al.
      Safety and immunogenicity of Cuban antipneumococcal conjugate vaccine PCV7-TT in healthy adults.
      ,
      • Linares-Pérez N.
      • Toledo-Romaní M.E.
      • Casanova M.F.
      • Paredes B.
      • Váldes-Balbín Y.
      • Santana-Mederos D.
      • et al.
      La nueva vacuna cubana antineumocócica, de las evidencias científicas disponibles, a la estrategia de evaluación clínica y de impacto.
      ). This vaccine contains seven highly prevalent serotypes worldwide, accounting for around 50–70% of isolate serotypes (
      • Johnson H.L.
      • Deloria-Knoll M.
      • Levine O.S.
      • Stoszek S.K.
      • Hance L.F.
      • Reithinger R.
      • et al.
      Systematic evaluation of serotypes causing invasive pneumococcal disease among children under five: the pneumococcal global serotype project.
      ,
      • Toraño-Peraza G.
      • Suárez D.
      • Abreu M.
      • Barreto B.
      • Toledo-Romaní M.E.
      • y Linares-Pérez N.
      Serotipos de Streptococcus pneumoniae responsables de enfermedad invasiva en niños cubanos.
      ). The composition of the vaccine candidate includes 2.2 μg of capsular polysaccharide from serotypes 1, 5, 14, 18C, 19F, and 23F, as well as 4.4 μg from serotype 6B, all conjugated to tetanus toxoid as the carrier protein and adsorbed on aluminum phosphate as adjuvant (
      • Linares-Pérez N.
      • Toledo-Romaní M.E.
      • Casanova M.F.
      • Paredes B.
      • Váldes-Balbín Y.
      • Santana-Mederos D.
      • et al.
      La nueva vacuna cubana antineumocócica, de las evidencias científicas disponibles, a la estrategia de evaluación clínica y de impacto.
      ). The quality specifications of the vaccine are in accordance with World Health Organization (WHO) requirements (
      • WHO
      Pneumococcal vaccines WHO position paper –2012–recommendations.
      ). The candidate vaccine has 24 months of demonstrated stability for the final product. The manufacturing process has been subject to several successful regulatory inspections by the national regulatory agency of Cuba. The preclinical research stages for this vaccine demonstrated immunogenicity and safety in animal models. Currently the technology has been scaled up and several batches have been produced for clinical trials.
      The safety and immunogenicity of the new vaccine candidate have been demonstrated in clinical trials conducted in adults, young children, and infants (
      • Dotres C.P.
      • Puga R.
      • Ricardo Y.
      • Brono C.R.
      • Paredes B.
      • Echemendía V.
      • et al.
      Safety and preliminary immunogenicity of Cuban pneumococcal conjugate vaccine candidate in healthy children: A randomized phase I clinical trial.
      ,
      • González N.
      • Paredes B.
      • Pérez S.
      • Mirabal M.
      • Rivero I.
      • González C.
      • et al.
      Safety and immunogenicity of Cuban antipneumococcal conjugate vaccine PCV7-TT in healthy adults.
      ). Preliminary results from a non-inferiority study on the protective efficacy of PCV7-T that included 1135 preschool children showed the following proportions of vaccinated children with a geometric mean titer (GMT) ≥0.35 (serotype-specific): 89% serotype 1, 77% serotype 5, 96% serotype 6B, 99% serotype 14, 96% serotype 18C, 99% serotype 19F, 96% serotype 23F. The prevalence of nasopharyngeal colonization was reduced from 32.2% (pre vaccination) to 6.5% (1 year post vaccination) (unpublished data).
      This article focuses on the potential contribution of the Cuban pneumococcal vaccination implementation strategy in the national and international context, shifting the paradigm from individual protection to the population effect of pneumococcal vaccination supported by a rigorous body of scientific evidence.

      The Cuban PCV implementation strategy

      The Cuban vaccine development and registration program for each population group represents a situation completely different to previous PCVs introduction experience around the world. The vaccine will be administered to children aged 1–5 years before being introduced for infant use.
      It is expected that the mass immunization of preschool children with high coverage will have a significant impact on nasopharyngeal carriage in those directly vaccinated and also on bacterial circulation at the population level. To estimate the impact on bacterial circulation, a prevalence in the vaccinated population at baseline of approximately 22–31.1% was assumed on the basis of nasopharyngeal colonization studies conducted in Cuba (
      • Toledo M.E.
      • Casanova M.F.
      • Linares-Pérez N.
      • García-Rivera D.
      • Toraño Peraza G.
      • Barcos Pina I.
      • et al.
      Prevalence of Pneumococcal Nasopharyngeal Carriage Among Children 2-18 Months of Age: Baseline Study Pre Introduction of Pneumococcal Vaccination in Cuba.
      ,
      • Toledo M.E.
      • Chávez D.
      • Casanova M.F.
      • Toraño G.
      • Linares N.
      Colonización nasofaríngea por neumococos en la población infantil cubana, evidencias basadas en estudios de prevalencia.
      ). A prevalence reduction range of between 25% and 60% (lower and upper reduction limits) has been reported in a systematic review and observational studies (
      • Loo J.D.
      • Conklin L.
      • Fleming-Dutra K.E.
      • Deloria Knoll M.
      • Park D.E.
      • Kirk J.
      • et al.
      Systematic review of the effect of pneumococcal conjugate vaccine dosing schedules on prevention of pneumonia.
      ,
      • Fleming-Dutra K.E.
      • Conklin L.
      • Loo J.D.
      • Knoll M.D.
      • Park D.E.
      • Kirk J.
      • et al.
      Systematic review of the effect of pneumococcal conjugate vaccine dosing schedules on vaccine-type nasopharyngeal carriage.
      ). The number of doses necessary to reduce one carrier is an average 9 for the population aged 3–5 years and 26 for the population aged 1–2 years. Generally, the vaccination of children will require 17 doses to reduce one carrier, which compares very favorably with 39 doses in infants to attend a similar effect on bacterial circulation at the population level.
      The initial Cuban PCV introduction strategy and associated studies will address numerous questions and expectations: (1) the importance of toddlers as a reservoir of pneumococci, (2) the direct and indirect effects of addressing toddler vaccination, (3) the herd immunity generated in infants, (4) the effects on nasopharyngeal colonization, and (5) the duration of this effect in the vaccinated and unvaccinated populations.
      From the standpoint of an international contribution to scientific knowledge, the Cuban pneumococcal vaccination implementation strategy was designed to obtain new knowledge that could shift the actual individual protection paradigm to a potentially more efficient population protection with PCV.
      There are several advantages to targeting young children for vaccination. Firstly, the vaccination of this age group through a vaccination campaign held over a short period of time and with high coverage will confer direct protection against the disease and target transmission within the community as a whole (
      • Schranz J.
      Pneumococcal conjugate vaccines: what do we know and what do we need?.
      ). Another at least empirical advantage of this proposed phased approach is related to the ‘reemergence phenomenon’, which is also considered an indirect effect of vaccination and is defined as an increase in the proportion of individuals in a population who harbor non-vaccine types in their nasopharynx after vaccine introduction (
      • Urueña A.
      • Pippo T.
      • Betelu M.S.
      • Virgilio F.
      • Giglio N.
      • Gentile A.
      • et al.
      Cost-effectiveness analysis of the 10- and 13-valent pneumococcal conjugate vaccines in Argentina.
      ,
      • Regev-Yochay G.
      • Hanage W.P.
      • Trzcinski K.
      • Rifas-Shiman S.L.
      • Lee G.
      • Bessolo A.
      • et al.
      Re-emergence of the type 1 pilus among Streptococcus pneumoniae isolates in Massachusetts, USA.
      ,
      • Pichon B.
      • Ladhani S.N.
      • Slack M.P.
      • Segonds-Pichon A.
      • Andrews N.J.
      • Waight P.A.
      • et al.
      Changes in molecular epidemiology of Streptococcus pneumoniae causing meningitis following introduction of pneumococcal conjugate vaccination in England and Wales.
      ). Key scientific questions on this topic are whether it could be possible to reduce the effect of serotype replacement in pneumococcal disease by reducing asymptomatic carriers and the vicious circle of antibiotic use and resistant strains in preschool children, and whether a new generation of pneumococcal vaccines targeting vaccine replacement serotypes could address this target population to reduce the global burden of disease at the population level.
      The follow-up of young vaccinated children and infants cohabiting with them will allow the direct and indirect effects to be explored using disease syndromes (meningitis, pneumonia, acute otitis media, and IPD) as the endpoint through a sentinel surveillance system. A panel survey will be held in vaccinated children and infants to identify changes in colonization associated with the vaccination and serotype replacement.
      Testing the hypothesis of whether it is possible to generate herd immunity in infants by addressing preschool children could on the one hand facilitate the design of new vaccines containing emerging serotypes (to administer to preschool children) and on the other hand be used to reduce the schedule in infants.
      The Cuban PCV implementation strategy provides the unique opportunity to include an effectiveness evaluation (direct and indirect effects) of a large population cohort in a stepped-wedge cluster trial. Selected children aged 1–5 years will be vaccinated and followed up alongside infants living at the study sites to explore changes in nasopharyngeal colonization. The short- and mid-term protection will be explored at 6 months, 1, 3, and 5 years after vaccination.
      In a second step, the vaccine will be licensed for use in infants. They will also be included as a target group as part of the Cuban expanded program on immunization. The safety, immunogenicity, non-interference with other vaccines, and booster effect will be explored in infants using a reduced dose schedule (3 + 0 and 2 + 1). The phase 1–2 clinical trial will involve 880 infants. Head-to-head comparisons will be done to demonstrate the non-inferiority of the new heptavalent Cuban vaccine against the licensed vaccine Prevnar 13, with respect to the seven common serotypes. This will be done taking into account WHO parameters for the registration and licensing of new pneumococcal vaccines (
      • WHO
      Pneumococcal vaccines WHO position paper –2012–recommendations.
      ). Changes in nasopharyngeal colonization post primo vaccination and post booster dose will be explored.
      To demonstrate the clinical efficacy on pneumococcal disease and pneumonia, meningitis syndromes, and acute otitis media, complementary epidemiological studies will be performed to include case–control (using the indirect cohort method) and case series studies based on the sentinel surveillance system implemented in six pediatric hospitals. The National Reference Laboratory will document changes in distribution of the circulating serotypes.
      Finally, and importantly, a cost-effectiveness evaluation will be included in the Cuban PCV implementation strategy. Cost-effectiveness studies will be implemented from the social perspective using the TRIVAC methodology (
      • Pichon B.
      • Ladhani S.N.
      • Slack M.P.
      • Segonds-Pichon A.
      • Andrews N.J.
      • Waight P.A.
      • et al.
      Changes in molecular epidemiology of Streptococcus pneumoniae causing meningitis following introduction of pneumococcal conjugate vaccination in England and Wales.
      ,
      • Clark A.
      • Jauregui B.
      • Griffiths U.
      • Janusz C.B.
      • Bolanos-Sierra B.
      • Hajjeh R.
      • et al.
      TRIVAC decision-support model for evaluating the cost-effectiveness of Haemophilus influenzae type b, pneumococcal and rotavirus vaccination.
      ,
      • Jauregui B.
      • Janusz C.B.
      • Clark A.D.
      • Sinha A.
      • Garcia A.G.F.
      • Resch S.
      • et al.
      ProVac Global Initiative: a vision shaped by ten years of supporting evidence-based policy decisions.
      ). International experts from the Pan-American Health Organization will monitor the quality of the primary information and results.

      Final comments

      There is no doubt that there are challenges for the new PCV7-T vaccine in the PCV13 era. However, the scientific contribution made by the Cuban implementation strategy could improve the body of evidence on pneumococcal vaccination. Taking into account that there is no agreement on the minimum schedule required for direct and indirect protection and that this could vary widely depending on the epidemiology of transmission, population structure, and mixing patterns, the results of clinical trials conducted in Cuba could provide new evidence on this topic. In the Cuban context, preschool children have a high burden of pneumococcal disease and nasopharyngeal colonization, influenced by an institutionalization regime, hence targeting them for vaccination could be efficient. The herd effect generated in infants by addressing preschool children will also provide new information.

      Declaration of interests

      The main authors of this paper – Nivaldo Linares-Pérez, PhD, Dagmar Garcia-Rivera, PhD, Darielys Santana-Mederos, BSc, Yury Valdés Balbín, BSc, and Vicente Verez-Bencomo, PhD – work at the center manufacturing the vaccine, the Finlay Vaccine Institute. María E. Toledo-Romaní, PhD and Anaí García-Fariñas, PhD work in the National Health System and do not have any contract or receive financing from the manufacturing center.

      Role of sponsors

      The Finlay Vaccine Institute and the National Funds for Sciences and Innovation from the Cuban Ministry of Science financed this work. Researchers from institutions in the health system will conduct and implement all studies.

      Acknowledgments

      The authors wish to thank all of the scientists, professionals, and specialists who are members of the working group on clinical research into the Cuban pneumococcal vaccine and the evaluation of its impact. The authors also wish to thank the institutions involved in the project for the new Cuban pneumococcal vaccine: The Tropical Medicine Institute “Pedro Kourí”, The National School of Public of Health, the National Vaccination Program of the Ministry of Public Health, and the Sentinel Surveillance Network of Pneumococcal Project at the La Habana, Santiago de Cuba, and Cienfuegos sites.

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