Reply to Varghese et al.'s response to Wu et al. — “Cost effectiveness analysis of infant pneumococcal vaccination in Malaysia and Hong Kong”

Introduction/background

In a recent research article, we evaluated the clinical and economic benefits of 13-valent infant pneumococcal conjugate vaccines (PCV13) compared to PCV10 in Malaysia and Hong Kong by using an age-stratified Markov cohort model with country-specific inputs. Our study showed that PCV13 remained a better choice over PCV10 in multiple sensitivity, scenario, and probabilistic analyses. A critique of our work by Varghese et al.¹ appeared in Human Vaccines & Immunotherapeutics. In this Reply, we have endeavored to respond to each point highlighted by Varghese.

Nasopharyngeal carriage and herd effect

Nasopharyngeal carriage (NPC) is an important factor in determining the extent of herd protection offered by pneumococcal vaccines.² Wu et al. cited a study by Cohen et al. in 2012³ as evidence for reductions in NPC associated with PCV13.⁴ Varghese et al. argue that this evidence is inconclusive, as the NPC carriage reduction among the 6 additional serotypes (ST) included in PCV13 over PCV7 was only significant for serotypes 19A and 7F. The study by Cohen et al.³ had a relatively short study period (6 months). During which, no isolates of serotype 6A, 1 and 5 were isolated from both study cohorts (those vaccinated with PCV7 and those vaccinated with PCV13). Hence a reduction of these serotypes would generally not be expected. However, for the other isolated serotypes, a statistically significant difference in the overall impact of the vaccine was reported. Also, at the time of the publication of our paper; the Cohen et al.³ paper remain the most relevant published information on nasopharyngeal carriage reduction of PCV13.

We agree with Varghese et al. that pneumococcal conjugate vaccines have a demonstrated role in reducing vaccine serotypes (VST) among unvaccinated individuals. The evidence for herd protection against IPD from PCV7 and PCV13 in all age groups has been documented in many environments against PCV13 VSTs, as well as all-cause disease.^5,6,7

As stated by Varghese et al., the Finland Invasive Pneumococcal disease (FinIP) vaccine trial⁸ demonstrated herd effect in unvaccinated children, aged 2 to 5 y old. Real world evidence of indirect effect associated with PCV10 is inconsistent and the effect does not appear to be sustained, possibly due to replacement disease caused by non PCV10 VSTs, such as 19A. In Finland, there was a decline in IPD caused by PCV10 vaccine serotypes in people over 5. All-cause IPD was not substantially impacted, however, with serotype 19A disease rates increasing.⁹ Further, in Brazil, while PCV10 use was associated with important reductions in IPD among children aged 2–23 months, there has been no impact on IPD rates in unvaccinated age groups.¹⁰

In a cost-effectiveness analysis in Japan, Suaya et al.¹¹ included varying levels of herd protection for PCV10 against IPD. Despite this allowance, PCV13 remained dominant in the comparison between the 2 vaccines.

Cross-protection against PCV10 non-vaccine serotypes

Serotype 19A became an important public health concern after the global introduction of the 7-valent pneumococcal conjugate vaccine (PCV7), as PCV7 vaccine-serotypes were reduced and 19A was likely able to fill the ecological niche left behind by the more invasive serotypes included in PCV7.^12,13,14,15

The assertion of cross- protection against serotype 19A through use of a PCV including serotype 19F is assumed to be caused by immunological cross-reactivity between serotypes 19F and 19A.¹⁶ PCV7, PCV10 and PCV13 all contain antigens against serotype 19F. There is little evidence of sustained cross-protection against 19A by a PCV containing 19F, however, and PCV13 is the only pneumococcal vaccine containing an antigen against 19A.

Case control studies, conducted early in PCV10 national immunization programs, showed reductions in serotype 19A caused disease in young children in Brazil (82.2%: 95% CI, 10.7, 96.4) and Finland (62%: 95% CI, 20, 85).^8,17 The results of these studies are contradicted by surveillance data reported from both of these countries, however. In Brazil, there has been an increase in 19A, 6A and 3 IPD cases following PCV10 introduction, with the number of cases in children < 5 y having increased in 2013 from the pre-PCV10 period.¹⁰ In Finland, 19A IPD cases in children < 5 y of age have remained similar between the years pre and post PCV10 introduction, although the numbers are small.⁹

In New Zealand, all 3 PCVs have been included in national immunization programs. PCV7 was introduced in 2008, PCV10 in 2011 and PCV13 in 2014.¹⁸ In 2013, 19A was the most prevalent IPD serotype in New Zealand, accounting for 76 IPD cases.¹⁸ As noted in the 2013 Invasive Pneumococcal Disease in New Zealand Surveillance Report, “Between 2011 and 2012, a significant increase in serotype 19A IPD was also observed in the < 2 y age group (from 6.4 to 10.6 per 100 000), but this rate decreased in 2013 to 5.8 per 100 000.”¹⁸ The 2014 New Zealand IPD Annual Report states, “Notably the increasing prevalence of IPD due to type 19A does not appear to have been affected by the change from PCV7 to PCV10, in contrast to some studies on the effectiveness of PCV10 which have suggested that the type 19F antigen in PCV10 provides some cross-protection against serotype 19A disease”.¹⁹ Within 1 y of replacing PCV10 with PCV13 in the national immunization program in 2014, the number of cases of 19A IPD in children < 5 y is nearly 4 times lower.

Since the introduction of PCV10, multiple countries with PCV10 National Immunization Programs (NIPs), have seen increases in 19A IPD among unvaccinated age groups. In Finland, there has been a 300% increase in 19A IPD incidence in adults over 65 y of age.⁹ In New Zealand there was a 42% increase in incidence of 19A IPD in people over 5.¹⁹ Finally, in Brazil the 3 serotypes included in PCV13, but not included in PCV10 (3, 6A, and 19A) experienced a fourfold rise in incidence from 2008 to 2013.¹⁰ This may be due to a lack of PCV10 effectiveness on NPC of 19A.²⁰ With unreliable impact on carriage, countries implementing PCV10 may have seen an increase in 19A carriage which eventually overwhelmed the limited protection offered through cross-reactivity.

In a 2016 pneumococcal subcommittee meeting, the UK Joint Committee on Vaccination and Immunisation,²¹ noted that, “evidence on the impact of the PCV13 childhood immunisation program (direct effectiveness, carriage, herd effects) from its use in the UK and elsewhere was extensive but the same granularity of data from high income settings with strong surveillance systems were not yet available for PCV10… and that pneumococcal serotype 19A disease had initially decreased following the introduction of PCV13 into the childhood immunisation program in the UK but had risen slightly recently, however larger rises had been noted in some countries using PCV10”.²¹

Effectiveness against all-cause pneumonia

Varghese et al. claim that it is a mistake to assume there would be increased protection against all-cause disease associated with higher-valent vaccines.¹ They further claim that when post-marketing clinical research shows differential effectiveness between vaccines in real world use, existence of confounding factors invalidates these findings. Within country data showing reductions in all-cause disease after replacing PCV7 with PCV13 in their pneumococcal NIPs speaks to improved protection against disease from higher-valent vaccines. In the United States, there was a 43% reduction in hospitalizations from pneumonia in children < 2 following implementation of PCV7. A further 27% reduction was observed in the 2 y following the introduction of PCV13, for a total reduction in pneumonia hospitalizations in children less than 2 of 72% (95% CI; 77%–65%) between the pre-PCV7 and PCV13 periods.⁷ In Israel there was a 47% reduction in pneumonia hospitalizations in children under 5 y of age between the pre-PCV7 and PCV13 time periods.²²

PCV13 contains 3 additional serotypes and is a more immunogenic vaccine than PCV10.²³ As there is substantial evidence demonstrating increasing protection against all-cause pneumonia for higher-valent vaccines, it is not invalid to assume that country specific vaccine serotype coverage is a proxy for differential effectiveness between PCV13 and PCV10.

Effectiveness against otitis media and effectiveness considerations for NTHi

Varghese et al. argue that PCV10 should be afforded some protection against nontypeable Haemophilus influenza (NTHi). In the COMPAS clinical trial evaluating the efficacy of PCV10, no significant effect of PCV10 on NTHi-clinically confirmed AOM was seen (point-estimate 21.5%; 95% CI: -43.4% to 57.0%).²⁴ A phase III double-blind, cluster-randomized trial in children < 18 months of age in Finland did not provide any evidence of reductions of NPC of NTHi associated with PCV10 vaccination.²⁰

Varghese et al. substantiate their assumption of efficacy by PCV10 against NTHi caused AOM with findings from the POET study on the efficacy of the experimental 11-valent pneumococcal protein D conjugate vaccine (PCV11).¹ There has been no evidence demonstrating that the impact on NTHi by PCV11 seen in the POET study can be extrapolated to PCV10 based on the Protein D conjugate material shared between the 2 vaccines.^25,26 PCV11 was never moved forward for development.

Per a recent study on the association between early episodes of AOM caused by S pneumoniae, and later, increasingly severe AOM caused by non-pneumococcal pathogens, “S pneumoniae is more frequently responsible for early episodes of otitis media and potentially initiates middle-ear damage, leading to a disease cascade that results in subsequent polymicrobial infections, which are generally associated with NTHi … Reduction of early episodes with PCVs can alter the pathogenic progression of otitis media, decreasing complex sequelae that are often associated with pathogens other than vaccine-type S pneumoniae, particularly NTHi”.²⁵ This effect may have been seen in Israel, where introduction of PCV7 and PCV13, led to a reduction in otitis media episodes caused by NTHi of 66%.^25,27,28

Effectiveness against serotype 3

Varghese et al. claim that there is no conclusive evidence that PCV13 provides herd protection for IPD caused by serotype 3. Recent evidence has emerged, however, demonstrating PCV13 serotype 3 IPD protection among unvaccinated populations in multiple countries. In the United Kingdom, a statistically significant decline in IPD caused by serotype 3 was seen among unvaccinated people in all age groups: in children < 5 (IRR: 0.32; 95% CI: 0.11–0.94); 5 to 64 y of age (IRR = 0.41; 95% CI: 0.41–0.62); as well as 65 y and older (IRR = 0.56; 95% CI: 0.45–0.73).⁶ Further, in the United States, data from the Center for Disease Control reported statistically significant reductions in serotype 3 IPD associated with PCV13 use (79.5%, CI: 30.3–94.8) between the years 2010 and 2014.²⁹ The most recent data from Germany³⁰ document PCV13 vaccine effectiveness for serotype 3 IPD as 73% (95% CI; 8 – 92) since the introduction of the vaccine. Based on this very recent data, it was valid for Wu et al. to include serotype 3 in the well demonstrated impact of PCV13 on IPD reductions in unvaccinated individuals.

Conclusion

The protection against serotype 3 conferred by PCV13 has been recognized by many countries as demonstrated in recent publications. It is also undeniable that a higher level of protection by PCV13 over PCV 7 was demonstrated by many surveillance systems worldwide. Countries around the world had decided to switch from PCV7 to PCV10 and then to PCV13 demonstrate the value of a higher valent vaccine. The reference of Varghese et al to PHiD-CV that has not been made available commercially which has a different carrier protein to the currently available PCV10 does not seem appropriate. Lastly, we agree on the importance of the ISPOR guidance on the use of evidence-based medicine principal. Pharmacoeconomic evaluation attempts to predict the value of technology, however, in the case of PCV 13, the value of the vaccine in reducing pneumococcal diseases has been well documented around the world.

Disclosure of potential conflicts of interest

DBCW and KKCL received funding from Pfizer Inc. to conduct this study. LWH is employee and shareholders in Pfizer Inc. The rest of authors reported no conflict of interest.

Acknowledgments

The authors are grateful to Margaret Moffatt (Pfizer) and Matt Wasserman (Pfizer) for their inputs in drafting this response letter.