When less is more: how many doses of PCV are enough?
Authors: Katherine L O'Brien
Journal: The Lancet Infectious Diseases (2017)

Pneumococcal conjugate vaccine (PCV) is an incredibly important, lifesaving vaccine, first licensed in 2000,1Advisory Committee on Immunization PracticesPreventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2000; 49: 1-35Google Scholar and recommended for infant routine use in the UK in 2006.2WHOPneumococcal conjugate vaccine for childhood immunization. WHO position paper.Wkly Epidemiol Record. 2007; 82: 93-104PubMed Google Scholar Since 2007 WHO has recommended it for inclusion in the routine infant immunisation schedule of all countries.3WHOPneumococcal vaccines. WHO position paper 2012.Wkly Epidemiol Record. 2012; 87: 129-144PubMed Google Scholar, 4Wahl B, O'Brien KL, Greenbaum A, et al. Global burden of Streptococcus pneumoniae in children younger than 5 years in the era of pneumococcal conjugate vaccines (PCV): 2000–2015. 10th International Symposium on Pneumococci and Pneumococcal Disease. Glasgow, Scotland. June 27–30, 2016. 67.Google Scholar Up to now, it has been rolled out in the national immunisation programmes of 141 countries (figure), has saved hundreds of thousands of lives,5Centers for Disease Control and PreventionPediatric/VFC vaccine price list.https://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-management/price-list/index.htmlGoogle Scholar and is projected to save millions in the decades to come as country introductions continue and coverage increases. However, PCV cost threatens this progress. In 2017 prices range from a low of US$3·05 per dose for the poorest countries of the world, supported by Gavi, the Vaccine Alliance,6UNICEFProduct menu for vaccines supplied by UNICEF for Gavi, the Vaccine Alliance.https://www.unicef.org/supply/files/Product_Menu31July2017.pdfGoogle Scholar to $169 per dose in the US private sector.7Pan American Health OrganizationExpanded program of immunization vaccine prices for year 2017.http://www.paho.org/hq/index.php?option=com_content&view=article&id=9561%3A2014-revolving-fund-prices&catid=839%3Arevolving-fund&Itemid=40714&lang=enGoogle Scholar Many middle-income countries, too wealthy for Gavi support, but unable to afford market driven prices, are left out. Furthermore, Gavi countries are starting to transition out of full support as their economies strengthen and may face harsh economic realities of PCV affordability into the future. Strategies to reduce PCV programme costs, without compromising disease protection need to be pursued. In The Lancet Infectious Disease, David Goldblatt and colleagues report much anticipated immunogenicity results of a novel two-dose PCV infant vaccination schedule compared with a standard infant three-dose schedule.8Goldblatt D Southern J Andrews NJ et al.Pneumococcal conjugate vaccine 13 delivered as one primary and one booster dose (1+1) compared with two primary doses and a booster (2+1) in UK infants: a multicentre, parallel group randomised controlled trial.Lancet Infect Dis. 2017; (published online Nov 22.)http://dx.doi.org/10.1016/S1473-3099(17)30654-0Summary Full Text Full Text PDF PubMed Scopus (75) Google Scholar As expected, immunogenicity of a single priming dose (1p) was inferior to two doses (2p). However, serotype-specific immunity following the booster dose of both schedules (1p + 1 and 2p + 1) was equivalent for most serotypes, showing that immunogenicity of the PCV booster dose is relatively independent of the number of priming doses received. This is why we care so much about the results of this immunogenicity trial, designed to answer a rather simple scientific question, but a pivotal policy question. We could be at the beginning of a clever "less is more" approach to pneumococcal disease control. The rationale for a reduced-dose PCV schedule centres on the observation that when three-dose or four-dose PCV infant schedules achieve prolonged, high coverage, vaccine serotype pneumococcal disease is virtually eliminated, as is vaccine serotype nasopharyngeal carriage in the community. The subsequent a priori risk for vaccine serotype pneumococcal disease in infants becomes extremely low because the organisms are no longer in widespread circulation. As long as community-wide immunity is sustained, there is limited rationale for inducing high immunity in the youngest infants, which requires using multiple PCV doses. Instead, immunising new birth cohorts with a single dose of PCV in the second year of life should succeed in maintaining high population immunity; adding a single PCV priming dose in early infancy, as was done in this study, not only enhances toddler immunity but is intended to also confer early, direct, albeit imperfect, immunity to these youngest infants in the event that they have exposure to vaccine serotype pneumococci before receiving their booster dose. This approach is a intended as a belt-and-braces strategy. The findings of this UK-based immunogenicity study have the potential to initiate a sequence of events that could reduce the number of PCV doses needed by programmes, provide enhanced global PCV access, and save billions of dollars in the process. But, much still needs to be assessed before that could happen. The effect of a 1p + 1 PCV maintenance programme would require careful monitoring through sustained, high quality pneumococcal disease surveillance as exists in the UK. However, questions about generalisability remain, especially for high disease burden settings. It is crucial to assess whether a 1p + 1 PCV schedule can prevent the acquisition of vaccine serotype pneumococcal colonisation among those immunised; this can only be established through studies in which vaccine serotype pneumococci are still in circulation. High, sustained coverage of the PCV booster dose is essential; worldwide, coverage with second dose measles vaccine, given in the second year of life, is only 60%.9WHO/UNICEFWHO/UNICEF estimates of national immunization coverage. Progress and challenges with achieving universal immunization coverage: 2016 estimates of immunization coverage (data as of July, 2017).http://www.who.int/immunization/monitoring_surveillance/who-immuniz.pdf?ua=1Google Scholar The epidemiological settings in which a PCV reduced dose approach might work are those in which adults contribute little to sustaining pneumococcal transmission; however, for high disease burden settings, this is often not the case. Finally, the effect of a reduced dose PCV schedule on vaccine serotype nasopharyngeal colonisation must be resilient to fluctuations in coverage or delays in dosing, which occur often in settings with fragile supply chains and frequent vaccine stock-outs. Studies to assess some of these issues are underway. If future evidence concludes that three PCV doses are not likely necessary for the maintenance of the public health and individual protection gains already achieved, vaccine policy makers should be fully willing to consider sustaining disease protection with the fewest possible doses. In spite of all the constraints on which countries might meet epidemiological conditions that would allow a switch to a 1p + 1 schedule, it is estimated that savings of roughly $1·5 billion could be accrued over a 10-year time period in Gavi eligible countries alone.10Gong W, Knoll MD, Hammitt L, et al. Reduced pneumococcal conjugate vaccine (PCV) dosing schedules for maintenance of impact: a review of the technical evidence and a policy analysis. 10th International Symposium on Pneumococci and Pneumococcal Disease, Glasgow, Scotland. June 27-30, 2016. 088.Google Scholar That would be a compelling "less is more" proposition. KLOB reports grants from Pfizer, GSK, Gavi, and BMGF, and other from Merck, outside the submitted work; and service on WHO SAGE. Pneumococcal conjugate vaccine 13 delivered as one primary and one booster dose (1 + 1) compared with two primary doses and a booster (2 + 1) in UK infants: a multicentre, parallel group randomised controlled trialOur findings show that for nine of the 13 serotypes in PCV13, post-booster responses in infants primed with a single dose are equivalent or superior to those seen following the standard UK 2 + 1 schedule. Introducing a 1 + 1 schedule in countries with a mature PCV programme and established herd immunity is likely to maintain population control of vaccine-type pneumococcal disease. Full-Text PDF Open AccessReassessing the 1 + 1 pneumococcal conjugate vaccine scheduleThe primary endpoint selected by David Goldblatt and colleagues,1 which was used to support a pneumococcal conjugate vaccine (PCV) programme consisting of one primary dose and one booster dose (1 + 1), is a poor indicator of protection during the first year of life, and contrary to O'Brien's Comment,2 this programme is not likely to be feasible for implementation in countries supported by Gavi, the Vaccine Alliance. Full-Text PDF