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A new paradigm in pneumococcal conjugate vaccination: moving from individual to herd protection

Open AccessPublished:April 24, 2017DOI:https://doi.org/10.1016/j.ijid.2017.04.015
      Immunization programs incorporating pneumococcal conjugate vaccines (PCV) have led to a dramatic decrease in invasive pneumococcal disease (IPD) due to vaccine serotypes, pneumonia, and otitis media in children receiving these vaccines. Consistent with the conjugate Haemophilus influenzae type B vaccine (Hib) experience (
      • Moulton L.H.
      • Chung S.
      • Croll J.
      • Reid R.
      • Weatherholtz R.C.
      • Santosham M.
      Estimation of the indirect effect of Haemophilus influenzae type b conjugate vaccine in an American Indian population.
      ), decreased nasopharyngeal (NP) carriage resulting in decreased transmission and the herd or indirect effect (decrease in disease in the unvaccinated) has also been seen with PCV, but the magnitude of this benefit has far surpassed initial expectations (
      • Lexau C.A.
      • Lynfield R.
      • Danila R.
      • Pilishvili T.
      • Facklam R.
      • Farley M.M.
      • et al.
      Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine.
      ,
      • 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.
      ,
      • Moore M.
      • Link-Gelles R.
      • Schaffner W.
      • Lynfield R.
      • Holtzman C.
      • Harrison L.H.
      • et al.
      Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance.
      ,
      • Von Gottberg A.
      • de Gouveia L.
      • Tempia S.
      • Quan V.
      • Meiring S.
      • von Mollendorf C.
      • et al.
      Effects of vaccination on invasive pneumococcal disease in South Africa.
      ). Two years following the introduction of PCV7 into the routine vaccination program in the USA using a 3 + 1 schedule (three infant doses at 2, 4, and 6 months of age and one toddler dose at 12–15 months of age), a profound effect was found in the unvaccinated: PCV7 prevented more than twice as many invasive cases through indirect effects than through its direct effect of protecting vaccinated children (
      • CDC
      Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease–United States, 1998-2003.
      ). This has been documented in other countries, including those using reduced dosing schedules such as 2 + 1, as well as in countries using the extended serotype vaccines, PCV10 and PCV13 (
      • Shiri T.
      • Datta S.
      • Madan J.
      • Tsertsvadze A.
      • Royle P.
      • Keeling M.J.
      • et al.
      Indirect effects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis.
      ). A reduction in NP carriage of vaccine serotypes, a precursor of the herd effect, was documented in the original 3 + 0 study of conjugate vaccination of infants in Africa (
      • Mbelle N.
      • Huebner R.E.
      • Wasas A.D.
      • Kimura A.
      • Chang I.
      • Klugman K.P.
      Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.
      ) and was confirmed in countries using 3 + 0 schedules (
      • Hammitt L.L.
      • Akech D.O.
      • Morpeth S.C.
      • Karani A.
      • Kihuha N.
      • Nyongesa S.
      • et al.
      Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya: findings from cross-sectional carriage studies.
      ). The mechanism for protection in the unvaccinated is due to the decrease and/or near elimination of vaccine serotypes from the nasopharynx. This in turns leads to decreased transmission of these serotypes and decreased disease. Thus, the effect on NP carriage, a non-disease state and critical precursor to disease, is key to the control of pneumococcal disease in countries unlikely to have immunization programs able to immunize all of their children.
      In this issue of the International Journal of Infectious Diseases,
      • Linares-Perez N.
      • Toledo-Romani M.
      • Santana-Mederos D.
      • et al.
      From individual to herd protection of pneumococcal vaccines: The contribution of Cuban PCVs implementation strategy.
      exploit the impact of conjugate vaccines on NP carriage to develop a public health immunization strategy for a new 7-valent tetanus-conjugated PCV. They propose to protect infants by vaccinating toddlers aged 1–5 years with a single dose, thus decreasing the doses required and increasing the cost-effectiveness of the PCV program. As with many novel ideas, this path is replete with unanswered questions and some challenges, but is certainly of considerable interest. We outline several key issues raised by this approach and the ongoing studies that are being conducted in this area to address them.
      First and foremost is the question of protection of the most at-risk group; can one count on indirect protection over individual, direct protection in young infants? Pondering this question leads to many more. Under what circumstances could one count on the herd effect to protect those most at risk? Should it be at the time after program maturation by which the circulation of vaccine serotypes is controlled and the goal would be maintenance of the induced protection, or could this be an effective strategy for PCV introduction for countries that have been unable to do so due to the high cost of PCV? What is the optimal timing for the older infant or toddler dose and what is the role of catch-up vaccination in the induction of the indirect effect? What level of vaccination in the community is needed? Coupled with all these scientific and programmatic questions is a crucial consideration − the need for optimal surveillance to assess impact.
      The greatest risk period for pneumococcal disease in children is under the age of 5 years and particularly under the age of 2 years. In the USA, in the pre-PCV era, the period of greatest risk was between 6 and 11 months of age (
      • Advisory Committee on Immunization Practices
      Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ), while in developing countries the highest risk may start earlier in infancy (
      • Mueller J.E.
      • Yaro S.
      • Ouedragogo M.S.
      • Levina N.
      • Njanpop-Lafourcade B.M.
      • Tall H.
      • et al.
      Pneumococci in the African meningitis belt: meningitis incidence and carriage prevalence in children and adults.
      ). A strategy to vaccinate older infants or toddlers would not target the group at highest risk for disease, but one that is a reservoir and serves as an efficient transmitter of the pneumococcus to the younger age group at highest risk of disease. Although evidence of herd protection in infants too young to be immunized (as demonstrated with the routine use of PCV7 in a four-dose strategy with a booster in the second year of life in the USA (
      • Poehling K.A.
      • Talbot T.R.
      • Griffin M.R.
      • Craig A.S.
      • Whitney C.G.
      • Zell E.
      • et al.
      Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine.
      ,
      • Olarte L.
      • Ampofo K.
      • Stockmann C.
      • Mason E.O.
      • Daly J.A.
      • Pavia A.T.
      • et al.
      Invasive pneumococcal disease in infants younger than 90 days before and after introduction of PCV7.
      ) and in South Africa with PCV7 followed by PCV13 in a three-dose strategy with a booster given at 9 months of age (
      • Von Gottberg A.
      • de Gouveia L.
      • Tempia S.
      • Quan V.
      • Meiring S.
      • von Mollendorf C.
      • et al.
      Effects of vaccination on invasive pneumococcal disease in South Africa.
      )) provides the theoretical framework for this strategy, it may be prudent to use this strategy as maintenance following control of the disease in this high risk group. This may be easily evaluable in countries using 3 + 1 and 2 + 1 schedules in which herd immunity has been well documented. Paradoxically, countries using 3 + 0 schedules, where certain invasive vaccine serotypes are still circulating despite PCV vaccination (
      • Jayasinghe S.
      • Menzies R.
      • Chiu C.
      • Toms C.
      • Blyth C.C.
      • Krause V.
      • et al.
      Long-term impact of a “3 + 0” Schedule for 7- and 13-valent pneumococcal conjugate vaccines on invasive pneumococcal disease in Australia, 2002-2014.
      ), may potentially achieve better control by changing to a 1 + 1 dosing schedule, since the booster dose could target children at peak times of carriage. Additionally, a strategy that relies on an indirect effect, using the proposed Cuban strategy of single doses to children aged 1–5 years, followed by a 1 + 1 strategy for infants and 9-month-olds or 1-year-olds, instead of three or four doses, may allow PCV introduction in countries that have not incorporated it into their national programs due to cost constraints.
      The optimal timing of an older infant or toddler dose is also a key consideration that is yet to be determined but is being addressed in several studies. To adequately target this dose, data on the group of children in whom interruption of vaccine serotype' transmission is critical are needed. Carriage rates by age and programmatic issues such as time of health care visits are key points needed for country decision-making. For developing countries, we have documentation from South Africa that the 9-month visit is programmatically feasible (
      • Von Gottberg A.
      • de Gouveia L.
      • Tempia S.
      • Quan V.
      • Meiring S.
      • von Mollendorf C.
      • et al.
      Effects of vaccination on invasive pneumococcal disease in South Africa.
      ), although compliance with this dose needs to be carefully addressed.
      Compliance with the 9-month dose raises the issue of the level of coverage required to ensure induction or maintenance of indirect protection. The percentage of children immunized at the time herd protection was documented in studies in the USA was 20–40% among American Indians for Hib conjugate vaccine (
      • Moulton L.H.
      • Chung S.
      • Croll J.
      • Reid R.
      • Weatherholtz R.C.
      • Santosham M.
      Estimation of the indirect effect of Haemophilus influenzae type b conjugate vaccine in an American Indian population.
      ), 67–75% with PCV7 in Massachusetts (
      • Loughlin A.M.
      • Hsu K.
      • Silverio A.L.
      • Marchant C.D.
      • Pelton S.I.
      Direct and indirect effects of PCV13 on nasopharyngeal carriage of PCV13 unique pneumococcal serotypes in Massachusetts’ children.
      ), and 58% among American Indians (
      • Grant L.R.
      • Hammitt L.L.
      • O’Brien S.E.
      • Jacobs M.R.
      • Donaldson C.
      • Weatherboltz R.C.
      • et al.
      Impact of the 13-valent pneumococcal conjugate vaccine on pneumococcal carriage among American Indians.
      ). Recent data from Spain, where PCV13 coverage in infants was reduced from 95% to 67–73% due to policy changes, demonstrate that overall reductions in IPD were maintained in all age groups of children (
      • Picazo J.
      • Ruiz-Contreras J.
      • Casado-Flores J.
      • Negreira S.
      • Baquero F.
      • Hernández-Sampelayo T.
      • et al.
      Effect of the different 13-valent pneumococcal conjugate vaccination uptakes on the invasive pneumococcal disease in children: Analysis of a hospital-based and population-based surveillance study in Madrid, Spain, 2007-2015.
      ).
      Access to PCVs is critical to achieve a decrease in childhood mortality, and decreasing the number of doses without compromising effectiveness may be a way to achieve sustainability of programs, especially in Gavi-graduating countries, and may be a means for vaccine introduction in middle-income countries unable to afford three-dose programs. In addition to the Cuban plan outlined by
      • Linares-Perez N.
      • Toledo-Romani M.
      • Santana-Mederos D.
      • et al.
      From individual to herd protection of pneumococcal vaccines: The contribution of Cuban PCVs implementation strategy.
      , a series of studies evaluating immunogenicity and NP carriage in 1 + 1 and 0 + 1 schedules of PCV10 and PCV13, compared to 2 + 1 and 3 + 0 schedules, are currently being funded by the Bill and Melinda Gates Foundation in India, South Africa, the UK, and Vietnam, and are under consideration in The Gambia. These should provide data to answer some of the questions outlined above.
      Lastly, the development of new, less expensive pneumococcal vaccines is another way to increase access and sustainability. Currently, PCVs have set a high bar of reducing NP carriage and inducing a herd effect. In view of this, would vaccines that do not impact carriage be acceptable? Currently, licensure standards are based on an immunological correlate of protection for IPD, but for non-conjugate vaccines, efficacy studies may be required and pose a significant logistic hurdle. In this new paradigm of moving from direct to indirect protection, could NP carriage be used as an endpoint for licensure? The “Case for Carriage”, a summary statement by the Pneumococcal Carriage Consortium (PneumoCarr) proposing NP colonization as a supplementary or alternative endpoint in vaccine licensure, laid the groundwork for this consideration (
      • Goldblatt D.
      • Ramakrishnan M.
      • O’Brien K.
      Using the impact of pneumococcal vaccines on nasopharyngeal carriage to aid licensing and vaccine implementation; A Pneumocarr meeting report March 27-28, 2012, Geneva.
      ).
      The new paradigm may be here soon. As described by
      • Linares-Perez N.
      • Toledo-Romani M.
      • Santana-Mederos D.
      • et al.
      From individual to herd protection of pneumococcal vaccines: The contribution of Cuban PCVs implementation strategy.
      , this encompasses using a herd strategy for introduction, coupled with broad catch-up vaccination and anticipated high rates of compliance. If this investigational tetanus-conjugated PCV7 is found to be effective in reducing NP carriage, it is likely that this strategy will successfully decrease IPD in Cuban children. We look forward to seeing their results and those of ongoing studies in other parts of the world.

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