Smart Scheduling: Optimizing National Immunization Programs to Achieve Maximum Impact

(See Brief Report by Blyth et al on pages 680–3.) Vaccination remains one of the most effective public health interventions for saving lives and promoting good health across all age groups. Over the past 3 decades, large steps have been taken in protecting children against the most common pathogens responsible for bacterial meningitis, namely Haemophilus influenzae type b (Hib), Neisseria meningitidis, and Streptococcus pneumoniae. This has been possible largely because of the successful implementation of conjugate-polysaccharide vaccines into national childhood immunization programs worldwide. Unlike polysaccharide-only vaccines, these conjugate vaccines are highly immunogenic from birth and induce immunological memory, leading to boosting of protective antibody responses with each dose and conferring long-term protection against invasive disease. Another major advantage of conjugate vaccines over polysaccharide-only vaccines is the prevention of carriage acquisition. Immunizing the age groups with the highest carriage rates leads to large reductions in invasive disease across all age groups through indirect (herd) protection resulting from reduced transmission to susceptible, unvaccinated individuals [1]. The long-term successes of conjugate vaccines are highlighted with the Hib conjugate vaccine, which was licensed in the late 1980s [2], and the meningococcal group C (MenC) conjugate vaccine, which was licensed in the late 1990s [3]. Both vaccines led to large, rapid, and sustained reductions in invasive disease across all age groups through a combination of direct and indirect protection. The first conjugate vaccine against pneumococcal disease was licensed in 2000 and, unlike the monovalent Hib and MenC conjugate vaccines, aimed to protect against 7 of almost 100 known pneumococcal serotypes that were responsible for the majority of invasive pneumococcal disease (IPD) cases in young children at the time. This 7-valent pneumococcal conjugate vaccine (PCV7) was first implemented in the United States according to the licensed schedule of 3 infant priming doses with a booster in the second year of life [4]. Other countries, including Australia and the United Kingdom, initially recommended the vaccine for high-risk groups only but eventually implemented the vaccines into their national immunization programs in 2005 and 2006, respectively; notably, the 2 countries recommended unique schedules of 3 + 0 [5]and 2 + 1 [6], respectively. Like Hib and MenC, the PCV7 immunization program was also associated with large and rapid reductions in IPD due to the 7 vaccine serotypes across all age groups, irrespective of the infant immunization schedule used [7]. The 3 + 0 schedule has now been widely adopted in many developing countries, while the 2 + 1 schedule is common across Europe and many other industrialized countries, although the United States continues to recommend a 3 + 1 schedule. In 2010, a 13-valent vaccine (PCV13) offering protection against 6 additional pneumococcal serotypes was licensed. Most countries replaced PCV7 with PCV13 in their national immunization programs because of increasing IPD cases due to some of the additional PCV13 serotypes (especially serotypes 3, 7F, and 19A) [8] Some countries opted to implement a 10-valent vaccine (PCV10), which offers protection against serotypes 1, 5, and 7F in addition to the PCV7 serotypes, but not serotypes 3, 6A, or 19A, which are also included in PCV13 [9] The impact of PCV13 was expected to be similar to that observed with PCV7 serotypes and, therefore, the same schedule was implemented in the respective countries. This, however, turned out not to be the case. The decline in IPD due to some of the additional PCV13 serotypes was lower than expected, both in the vaccinated (direct impact) and unvaccinated (indirect impact) cohorts [7, 10, 11]. In Australia, 3 years after PCV13 implementation, there was only an 11% reduction in overall IPD incidence compared with the pre-PCV13 baseline; in contrast, there was a 42% decline due to PCV7 in an equivalent PCV7 period [7]. In the United Kingdom, IPD incidence due to the additional PCV13 serotypes declined across all age groups during the first 4 years of the program and then plateaued, mainly because of a large increase in serotype 3 IPD [10]. A 3-dose infant priming schedule, especially when given at 2-month intervals as used in Australia, would be expected to induce higher serotype-specific antibody responses after primary immunization and, therefore, confer better short-term protection against IPD [12]. This would explain the relatively small number of vaccine-failure cases among 6- to 11-month-olds, both in Australia (3 + 0 schedule) and the United States (3 + 1 schedule), especially when compared with the United Kingdom (2 + 1 schedule), where most vaccine-failure cases occurred in infants after completing their 2-dose priming schedule and before their 12-month booster [13]. It is important to consider why the success of PCV7 was not emulated by PCV13 in many countries, including Australia where the same 3 + 0 infant schedule was implemented for both vaccines. Serotype-specific antibody responses after PCV13 are generally lower than PCV7 when given at the same schedule, even for some of the serotypes common to both vaccines [14]. Additionally, protection against invasive disease will depend on the balance between the serotype-specific antibody concentration induced by the vaccine and the antibody threshold required to kill that serotype. While 0.35 μg/mL is generally accepted as the correlate of protection for individual pneumococcal serotypes, the estimated correlate of protection among infants receiving a 2 + 1 PCV13 schedule, for example, was as low as 0.16 μg/mL for serotype 6A, higher for 19A (1.00 μg/mL) and 19F (1.17 μg/mL), and as high as 2.83 μg/mL for serotype 3 [15]. It is, therefore, not surprising that the latter three serotypes are currently the most common causes of vaccine failure, irrespective of the PCV13 immunization schedule used. The increase in pneumococcal vaccine failure cases observed in Australia, mainly after 12 months of age, has not been observed in countries that routinely offer a booster in the second year of life. The number of vaccine-failure cases compared with the cohort vaccinated in Australia annually, however, was very small (3.9 per 100 000), even though the PCV13 vaccine failure cases did account for 21% of total IPD cases in 6- to 59-month-olds during 2012–2017 as reported in this issue of Clinical Infectious Diseases [16]. A more important consequence of waning immunity after the Australian 3 + 0 schedule, however, is the potential impact on the indirect (herd) protection. Countries that have switched from PCV7 to PCV13 have generally observed a lower indirect (herd) impact with the latter vaccine [10]. Australia, however, has reported lower indirect impact with both PCV7 and PCV13 when compared with countries that routinely offer a booster in the second year of life (Table 1). Reduction in Invasive Pneumococcal Disease in Vaccinated and Unvaccinated Cohorts Across 3 Countries With Different 13-Valent Pneumococcal Conjugate Vaccine Infant Immunization Schedules Abbreviations: IPD, invasive pneumococcal disease; PCV13, 13-valent pneumococcal conjugate vaccine. Reduction in Invasive Pneumococcal Disease in Vaccinated and Unvaccinated Cohorts Across 3 Countries With Different 13-Valent Pneumococcal Conjugate Vaccine Infant Immunization Schedules Abbreviations: IPD, invasive pneumococcal disease; PCV13, 13-valent pneumococcal conjugate vaccine. Young children, mainly those aged less than 2 years, are the primary carriers and transmitters of pneumococci. Maintaining high vaccine uptake in this age group is vital to ensure high indirect protection. Antibody concentrations with conjugate vaccines reach a lower peak and wane more quickly after primary immunization than after a booster dose in the second year of life. Countries recommending conjugate vaccines without a booster dose are not only more likely to experience higher rates of vaccine failure with time after vaccination but, since much higher serotype-specific antibody concentrations are required to prevent carriage compared with invasive disease [18], those receiving primary immunization only may be more susceptible to carriage of some of the vaccine serotypes as vaccine-induced serotype-specific antibodies wane with time since vaccination. An infant primary immunization schedule without a booster could, therefore, potentially compromise the indirect (herd) impact of the program, which will affect a much larger population compared with the direct protection offered to the vaccinated cohort. This has implications in terms of disease burden and healthcare utilisation not only for IPD but also for noninvasive disease, including nonbacteraemic pneumonia, otitis media, and sinusitis [7]. From a health economic perspective, the relatively small number of vaccine failures after the 3 + 0 schedule even with PCV13 would not justify adding a 12-month booster in Australia. Shifting one of the infant priming doses to the booster dose would, however, be cost neutral and can be justified by the extensive experience already gained with the 2 + 1 schedule in the United Kingdom and other industrialized countries [10]. In a systematic review evaluating PCV immunogenicity given at different schedules, although antibody concentrations were higher following 3-dose compared with 2-dose infant priming schedules, the pre- and postbooster antibody concentrations were generally similar regardless of whether 2 or 3 primary doses were given [12]. The systematic review also reported that antibody concentrations were significantly higher for all serotypes when the third dose was administered in the second year (2 + 1 schedule) compared with all 3 doses given by 6 months of age (3 + 0 schedule) [12]. The improved indirect protection afforded by the 2 + 1 schedule over the current Australian 3 + 0 schedule will not only help protect older children and adults (including at-risk individuals) but also provide additional protection to all those children who have been immunized with the 3 + 0 schedule since 2004. Moreover, the indirect protection will help protect infants who are too young to be vaccinated and those who will be receiving 2 priming doses until their 12-month booster. Breakthrough cases among 6- to 11-month-olds, however, will need to be monitored because this age group is more susceptible to developing meningitis compared with other clinical presentations as observed in the United Kingdom [10]. This is particularly pertinent to Australia where PCV13-type meningitis in infants aged 6 months and older has been virtually eliminated [7]. The high-quality, long-term IPD surveillance in Australia provides an ideal opportunity to objectively monitor the effects of shifting from a 3 + 0 to a 2 + 1 schedule in a national immunization program. Their findings will be of great importance to other countries with similar schedules. Interestingly, the United Kingdom has recently opted to move from a 2 + 1 to a 1 + 1 schedule at 3 and 12 months of age [19] on the basis that maximum herd protection has already been achieved for the PCV13 serotypes and that, although infants will only receive a single PCV13 dose which is less immunogenic than a 2-dose schedule, they will benefit from the indirect protection afforded by the 12-month booster since the postbooster responses are similar after both the 1 + 1 and 2 + 1 schedules [20]. Having high-quality surveillance ensures that the national immunization program can be rapidly modified to respond to disease changes. Potential conflicts of interest. The authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.