Comprehensive value assessments for new pediatric pneumococcal conjugate vaccines

Abstract

Although the incidence of invasive pneumococcal disease (IPD) and acute otitis media (AOM) in young children has decreased since the introduction of pneumococcal conjugate vaccines (PCVs), the subsequent emergence of non-vaccine Streptococcus pneumoniae serotypes and the persistence of certain vaccine serotypes both contribute to substantial residual pneumococcal disease. There is a need for the development of new pneumococcal vaccines to address the clinical and economic burden presented by emerging non-vaccine serotypes, while maintaining suppression of serotypes in existing vaccines. To assess the full value of next-generation vaccines, public health evaluations must consider epidemiological and economic data across all vaccine serotypes, including those included in existing vaccines and those unique to the new product. This is supported by two recent analyses that estimated the health and economic burden of IPD (in the United States and Europe) and AOM (in the United States only) associated with the serotypes in V114, a 15-valent pneumococcal conjugate vaccine (PCV15), which contains all serotypes in the licensed 13-valent pneumococcal conjugate vaccine (PCV13) as well as the unique serotypes 22 F and 33 F and was recently approved for use in adults in the US. The analyses demonstrated considerable health and economic burden associated with PCV13 serotypes, as well as increasing burden associated with serotypes 22 F and 33 F. In addition to addressing the burden of non-vaccine serotypes, ability to maintain or improve protection against disease caused by serotypes in existing vaccines will be an important consideration for decision makers.

Keywords:

• Invasive pneumococcal disease
• acute otitis media
• pneumococcal conjugate vaccines
• health and economic burden
• vaccine development

JEL CLASSIFICATION codes:

• I10
• I1
• I
• I19

This article is related to:

Health and economic burden of invasive pneumococcal disease associated with 15-valent pneumococcal conjugate vaccine serotypes in children across eight European countries

Introduction

The incidence of pneumococcal disease (PD) in children has decreased substantially since the introduction of the first pneumococcal conjugate vaccine (PCV) in 2000.¹ The vaccine, which contained seven of the Streptococcus pneumoniae serotypes most commonly associated with PD in children (7-valent PCV [PCV7]), was highly effective in reducing the disease caused by these serotypes.^1,2 The subsequent introduction of a 13-valent PCV (PCV13) a decade later resulted in further reductions in the incidence of PD, due to decreases in disease caused by the additional six serotypes in this vaccine.^3,4 However, owing to the emergence of disease caused by non-vaccine serotypes, as well as the persistence of certain vaccine serotypes,^1,5 PD remains an important global cause of morbidity and mortality in children,⁶ and represents a significant economic burden.^7,8 There is currently an unmet need for new pneumococcal vaccines to address this residual disease burden,⁹ while maintaining suppression of serotypes in existing vaccines. Vaccines currently in late-stage clinical development for pediatric use, including V114 (VAXNEUVANCEⁱ) and a 20-valent PCV (PREVNAR 20ⁱⁱ), both recently approved for use in adults in the US.^10–12

Considerations for the development of new PCVs

The phenomenon of serotype replacement following the introduction of a pneumococcal vaccine is well documented.¹³ After the introduction and scale up of PCV7 in routine immunization programs, an increase in the proportion of invasive PD (IPD) caused by non-PCV7 serotypes was observed across numerous different regions, leading to the development of PCV13 (which contains additional serotypes 1, 3, 5, 6 A, 7 F, and 19 A, as well as the PCV7 serotypes 4, 6B, 9 V, 14, 18 C, 19 F, and 23 F).^1,13 Now that PCV13 has been used in routine immunization schedules for several years, a similar pattern is being observed, with several non-PCV13 serotypes beginning to emerge as important causes of IPD in pediatric populations. For example, in 2017, serotypes 33 F and 22 F were together responsible for 16.7% of all IPD cases in children aged <5 years in the United States.¹⁴ These serotypes have also recently become common causes of IPD in children in Europe, together with others such as 8, 24 F, 12 F, 23B, and 10 A.¹⁵ New PCVs should address the burden represented by these emerging non-PCV13 serotypes.

There is also increasing evidence to suggest that the effectiveness of PCV13 against IPD caused by certain vaccine serotypes may be insufficient. Several studies have demonstrated a lack of effectiveness against IPD caused by serotype 3,^1,4,16 and the prevalence of IPD caused by serotype 19 A has plateaued in recent years,^5,14,15 after an initial decline following the introduction of PCV13.¹⁷ The incidence of IPD caused by serotype 19 F, which was included in PCV7 and decreased substantially after that vaccine was introduced, is again increasing.^14,15,17 Furthermore, it is recognized that higher-valent PCVs elicit lower levels of antibodies relative to first-generation PCVs for the shared serotypes.¹⁸ ‘Geometric mean concentration (GMC) creep’, whereby serotype-specific immune responses may decrease further as more serotypes are added, continues to be a concern with expanded valency vaccines.⁹ As such, GMC creep with new PCVs may represent a particular risk of additional breakthrough disease due to the persistent vaccine serotypes described above. Therefore, ensuring maintained or improved effectiveness against serotypes included in current vaccines is an important consideration for new PCVs.

Decision makers assessing next-generation PCVs will need to weigh the benefits of the additional serotypes included against the potential for breakthrough disease if serotype-specific immune responses are not maintained. As such, technology assessments that consider epidemiological and economic data across all serotypes included in new vaccines, rather than only the additional serotypes, will be key to future decisions on pneumococcal vaccination recommendations.

Assessing the value of new PCVs

In a recent issue of the Journal of Medical Economics, we presented the findings from two analyses that estimated the health and economic burden of IPD (in the United States¹⁹ and Europe²⁰) and acute otitis media ([AOM] in the United States only) associated with the serotypes in V114, which is currently in late-stage clinical development for pediatric use. The vaccine contains all serotypes in PCV13, as well as two unique serotypes, 22 F and 33 F. These two emerging serotypes have high potential to cause invasive disease,²¹ and serotype 33 F is associated with multidrug resistance.²²

Our analyses quantified the health and economic burden of PD attributable to the 15 serotypes in V114 in two hypothetical unvaccinated birth cohorts over a 20-year period. Our first analysis examined the burden of IPD and AOM caused by the 15 serotypes in the United States, and our second analysis evaluated IPD burden across eight European countries (Denmark, France, Germany, Italy, Norway, Spain, Switzerland, and the United Kingdom). We used a Markov model with epidemiological and cost inputs taken from published literature and surveillance reports, such as age-specific disease incidence and serotype distribution, direct medical costs, and indirect costs, including productivity losses among caregivers and lifetime productivity losses associated with premature death. Cases, mortality, and costs were estimated for three time periods: prior to the introduction of PCV7 (pre-PCV7 period), prior to the introduction of PCV13 (pre-PCV13 period), and after the introduction of PCV13 (post-PCV13 period).

In both the United States and European analyses, the 15 pneumococcal serotypes included in V114 contributed to a substantial number of cases and deaths during all three time periods. Most cases were attributable to PCV7 serotypes in the pre-PCV7 period; however, IPD cases associated with the six additional serotypes in PCV13 increased from the pre-PCV7 period to the pre-PCV13 period. In the United States, the proportion of IPD cases attributable to serotypes 3, 7 F, and 19 A, and AOM due to serotypes 3 and 19 A, increased in the pre-PCV13 period. In Europe, the proportion of IPD cases attributable to serotypes 1, 3, 7 F, and 19 A increased in the pre-PCV13 period. The proportion of IPD cases attributable to serotypes 22 F and 33 F, which are unique to V114, increased in the pre-PCV13 and post-PCV13 periods compared with the pre-PCV7 period in both analyses; in the United States, AOM due to serotype 33 F also increased in the post-PCV13 period. Further increases in the proportion of cases due to serotype 3 were observed in the post-PCV13 period in both regions.

The serotypes in V114 were also associated with substantial direct medical and indirect costs. Total costs (discounted at 3%) in the pre-PCV7 period were $1.7 billion due to IPD and AOM in the United States and €109 million due to IPD in Europe, the majority of which were attributable to PCV7 serotypes. Overall, there were net increases of $462 million and €24 million in the pre-PCV13 period compared with the pre-PCV7 period due to the six additional serotypes in PCV13. Total costs associated with serotypes 22 F and 33 F in the post-PCV13 period were $23 million and €5 million (31% and 26% of the total, respectively).

Our analyses demonstrate the considerable health and economic burden associated with serotypes in currently licensed vaccines and highlight the importance of maintaining and improving protection while expanding coverage to non-vaccine-type serotypes. Although our analyses had some limitations, such as the exclusion of non-bacteremic pneumococcal pneumonia, post-meningitis sequalae, and certain direct non-medical and indirect costs from the model, as well as the exclusion of AOM from the European analysis, these are likely to have caused our estimates to be overly conservative; therefore, the true value of vaccination against the 15 serotypes in V114 may be greater than our estimates. Notably, our analyses did not include the impact of PCVs on nasopharyngeal carriage or transmission of pneumococcal infections from person to person, and so did not account for the indirect protective effect of PCVs on unvaccinated children or adults. Invasiveness of specific serotypes and potential indirect effects of vaccination are also important considerations for the development of new PCVs. There is a need for more robust serotype-specific incidence data, particularly for non-invasive pneumococcal disease and nasopharyngeal carriage, to inform future value assessments for new PCVs.

Conclusions

Evaluations of the public health and economic value of next-generation pediatric pneumococcal vaccines should not be limited to disease prevented by non-vaccine serotypes. The full value of new pneumococcal vaccines must account for both the serotypes included in previously licensed vaccines, as well as emerging non-vaccine type serotypes. In addition to addressing the burden of non-vaccine serotypes, maintaining or improving protection against disease caused by PCV7 and PCV13 serotypes should be an important consideration for countries to include in their decision-making.

Transparency

Declaration of funding

This analysis was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Declaration of financial/other interests

All authors are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ, USA.

JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors contributed equally.

Acknowledgements

Medical writing support, including assisting authors with the development of the initial draft and incorporation of comments, was provided by Rachel Wright, PhD, and editorial support, was provided by Ian Norton, PhD, all of Scion, London, supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, according to Good Publication Practice guidelines (Link). Ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

Notes

i VAXNEUVANCE is a trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

ii PREVNAR 20 is a trademark of Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer, Inc., Philadelphia, PA, USA.