Infant protection from invasive Haemophilus influenzae type b disease using the PRP-OMPC conjugate vaccine: An update

ABSTRACT

Invasive disease caused by Haemophilus influenzae type b (Hib) is a major health concern, particularly in children under 5 years of age and vulnerable populations. Use of Hib conjugate vaccines has significantly reduced the incidence of Hib disease. Among these, the polyribosylribitol phosphate-outer membrane protein complex (PRP-OMPC) conjugate has demonstrated uniquely robust immunogenicity in infants compared to PRP conjugated to tetanus toxoid. Vaxelis, using the PRP-OMPC conjugate, was well tolerated and immunogenic as shown through the clinical development program. Additional studies that are recently published address previously open questions regarding Vaxelis, including immunogenicity after the first infant dose, co-administration with meningococcal B vaccine, and interchangeability with other hexavalent vaccines. This brief review summarizes recently published Vaxelis data, with potential implications for ongoing control of invasive Hib disease in Europe.

Introduction

Haemophilus influenzae (H. influenzae) is a Gram-negative bacterium that can colonize the nasopharynx and subsequently infect other tissues, causing upper and lower respiratory infections and invasive diseases such as meningitis, septicemia, and epiglottitis. Among the multiple types of H. influenzae, H. influenzae type b (Hib) was the prominent cause of invasive disease before several anti-Hib vaccines were developed and deployed for use in infants and young children. Certain vulnerable/special populations, such as preterm infants, American Indian and Alaska Native (AI/AN), and Australian indigenous peoples, experienced even higher rates of invasive disease compared to the general population.^1–4 Hib is associated with high case-fatality rates in unvaccinated or under-vaccinated individuals, with young children under 5 years of age and older adults at particularly high risk.^5–8

The Hib polysaccharide capsule polyribosylribitol phosphate (PRP) is the major virulence factor for Hib and was used in the development of the first Hib vaccines. Since polysaccharide antigens produce mostly T cell-independent antibody responses and therefore have lower immunogenicity in infants,^9,10 various protein conjugates have been used with PRP to stimulate T-dependent immunity and long-lasting protection from Hib disease.^11,12 Standalone Hib conjugate vaccines were first licensed for use in children in the 1980s and were highly effective, reducing invasive Hib disease > 90% when included as part of national immunization programs (NIPs). Hib vaccination directly reduced all-cause meningitis morbidity as well as all-cause pneumonia-related hospitalizations.^7,13–15 The two PRP conjugates that have been used through the present day in the United States and the European Union include the outer membrane protein complex (OMPC) from Neisseria meningitidis, and tetanus toxoid (T) from Clostridium tetani. While PRP-OMPC and PRP-T conjugates are both immunogenic, PRP-OMPC demonstrated increased Hib immunogenicity in infants after the first dose compared to PRP-T conjugates.^12,16–18 As such, this conjugate is preferentially used in vulnerable infants at higher risk for early and more severe Hib infection.¹⁹

Changes to Hib vaccine recommendations have occurred over time. After a broad programmatic change in the U.S. from monovalent PRP-OMPC to PRP-T vaccine in the 1990s, a marked increase in Hib disease incidence in Alaskan infants was observed.²⁰ This increase was subdued by a return to the monovalent PRP-OMPC vaccine and prompted a preferential recommendation of PRP-OMPC for Hib vaccination in this population. The increased disease incidence was suggested to be related to differential ability to control nasopharyngeal carriage of Hib, with higher Hib carriage observed in PRP-T vaccinated children.²⁰ In Australia, PRP-OMPC was initially recommended and resulted in a substantial decline in invasive Hib disease. However, recommendations switched to PRP-T in 2008–2009 due to availability of a PRP-T containing combination vaccine and a desire to simplify the pediatric vaccination program.²¹

Hib conjugate vaccines are incorporated into a combination of hexavalent vaccines (HVs) which have additional benefits such as fewer injections for infants, simplifying vaccine transportation, storage and administration time, as well as improving vaccination coverage.^22,23 Currently available HVs in the EU include Vaxelis® (DTaP5-IPV-HepB/Hib; MCM Vaccine B.V.), Hexyon/Hexaxim® (DTaP2-IPV-HepB/Hib; Sanofi), and Infanrix® hexa (DTaP3-IPV-HepB/Hib; GlaxoSmithKline). Only Vaxelis is available in the United States (U.S.). The composition of these HVs is shown in Table 1. In their respective clinical development programs, all three HVs were assessed in comparison to existing pentavalent combination vaccines and other HVs as relevant.^24–26 Published studies have demonstrated HVs to be generally well tolerated and immunogenic,^{22,24,26–29} with robust estimates of vaccine effectiveness reported.^30–32 All three HVs additionally use acellular pertussis antigens (Table 1) with favorable estimates of effectiveness against pertussis.^33,34 There are several different vaccination schedules approved for use of HVs depending on local recommendations, with most countries in Europe utilizing 2 infant and 1 toddler (2 + 1) or 3 infant and 1 toddler (3 + 1) regimens.³⁵

Table 1.

Hexavalent combination vaccines composition (adapted from Guerra, et al.). Hib component is highlighted.

Vaxelis (DTaP5-IPV-HepB-Hib)		Hexyon/Hexaxim (DTaP2-IPV-HepB-Hib)		Infanrix Hexa (DTaP3-IPV-HepB/Hib)
Antigen	Amount	Antigen	Amount	Antigen	Amount
Diphtheria toxoid	≥20IU	Diphtheria toxoid	≥20IU	Diphtheria toxoid	≥30IU
Tetanus toxoid	≥40IU	Tetanus toxoid	≥40IU	Tetanus toxoid	≥40IU
Bordetella pertussis antigens - Pertussis toxoid (PT) - Filamentous hemagglutinin (FHA) - Pertactin (PRN) - Fimbriae Types 2 and 3 (FIM2/3)	20ug 20ug 3ug 5ug	Bordetella pertussis antigens - Pertussis toxoid (PT) - Filamentous hemagglutinin (FHA) - Pertactin (PRN) - Fimbriae Types 2 and 3 (FIM2/3)	25ug 25ug Not in vaccine Not in vaccine	Bordetella pertussis antigens - Pertussis toxoid (PT) - Filamentous hemagglutinin (FHA) - Pertactin (PRN) - Fimbriae Types 2 and 3 (FIM2/3)	25ug 25ug 8ug Not in vaccine
Hepatitis B surface antigen	10ug	Hepatitis B surface antigen	10ug	Hepatitis B surface antigen	10ug
Poliovirus (inactivated) - Type 1 (Mahoney) - Type 2 (MEF-1) - Type 3 (Saukett)	40 D antigen units 8 D antigen units 32 D antigen units	Poliovirus (inactivated) - Type 1 (Mahoney) - Type 2 (MEF-1) - Type 3 (Saukett)	40 D antigen units 8 D antigen units 32 D antigen units	Poliovirus (inactivated) - Type 1 (Mahoney) - Type 2 (MEF-1) - Type 3 (Saukett)	40 D antigen units 8 D antigen units 32 D antigen units
- Haemophilus influenzae type b polysaccharide - Polyribosylribitol phosphate (PRP) conjugated to meningococcal protein	3ug 50ug	- Haemophilus influenzae type b polysaccharide - Polyribosylribitol phosphate (PRP) conjugated to tetanus protein	12ug 22-36ug	- Haemophilus influenzae type b polysaccharide - Polyribosylribitol phosphate (PRP) conjugated to tetanus protein	10ug 25ug

While invasive Hib disease remains largely controlled in countries with Hib vaccination as part of their NIPs, in recent years surveillance data have shown increases in some European countries. Surveillance results from the 2012–2016 and 2017–2021 time periods in Italy showed a trend toward increasing numbers of invasive H. influenzae cases, with Hib as the most common capsular type and children under one year of age having the highest incidence rate per 100,000 residents.^36,37 A study of H. influenzae isolates in Portuguese children from 2010–2021 reported Hib as the most commonly isolated capsular type, and more overall invasive disease cases and Hib cases were reported in the study after 2016.³⁸ In France, an analysis of invasive H. influenzae isolates from 2017–2019 reported that 11.1% of invasive isolates were Hib with approximately two-thirds of the Hib cases occurring in children under 5 years of age.³⁹ An increase in cases has also been observed in the Netherlands.⁴⁰ In contrast, reports from the United Kingdom (UK), U.S., Germany, and Australia suggest strong ongoing control of invasive Hib disease.^2,31,41–43 While invasive Hib cases have been reported in both children and adults, the preponderance of cases has occurred in children under five years of age. The purpose of this review is to summarize recently published studies of Vaxelis (containing PRP-OMPC), focusing on its Hib immunogenicity that, considering the recent increases in invasive Hib disease, has become critical to understand.

Results

Pivotal trials with DTaP5-IPV-HepB-Hib

DTaP3-IPV-HepB/Hib was the first approved HV along with Hexavac (which was subsequently discontinued), followed by DTaP2-IPV-HepB-Hib and DTaP5-IPV-HepB-Hib. As shown in Table 1, the three HVs target the same pathogens but have different product profiles. For instance, DTaP5-IPV-HepB-Hib contains five pertussis antigens, DTaP3-IPV-HepB-Hib contains three, and DTaP2-IPV-HepB-Hib two. Notably, DTaP5-IPV-HepB-Hib contains PRP-OMPC conjugate whilst the other HVs are PRP-T conjugates. In pivotal trials, DTaP5-IPV-HepB-Hib demonstrated strong PRP immunogenicity, with post-primary series immune responses (whether two-dose or three-dose) generally higher than DTaP3-IPV-HepB/Hib for both short term (≥0.15 μg/mL) and long term (≥1.0 μg/mL) immunogenicity thresholds.⁴⁴ Following the toddler dose (given at 11–12 months) anti-PRP levels were generally higher for DTaP3-IPV-HepB/Hib, while both HVs demonstrated a high and comparable proportion of participants with anti-PRP response rates at or above the long-term immunogenicity threshold.^44–46

Recent studies evaluating PRP responses of DTaP5-IPV-HepB-Hib

While the DTaP5-IPV-HepB-Hib clinical development program investigated anti-PRP antibody levels in 2 + 1 and 3 + 1 vaccination schedules, important unanswered questions remained. Additional studies have been conducted to address existing data gaps and further evaluate the immunogenicity of DTaP5-IPV-HepB-Hib. The anti-PRP responses were of particular interest. The results of these studies are discussed below, and a summary is provided in Table 2.

Table 2.

Summary of key findings from recently published studies using the PRP-OMPC conjugate.

Study	Vaccination schedule	Study vaccines	Anti-PRP GMCs following primary doses (95% CI)*	Anti-PRP GMCs following toddler dose (95% CI)*
Jackson, et.al. NCT04978818	2 m, 4 m, 6 m (6 m dose for DTaP5-IPV-HepB-Hib only)+	DTaP5-IPV-HepB-Hib Monovalent PRP-OMPC	At 3 m of age (post-dose 1): DTaP5-IPV-HepB-Hib: 0.41 (0.33–0.52)μg/ml Monovalent PRP-OMPC: 0.39 (0.31–0.50)μg/ml At 7 m of age (post-dose 3): DTaP5-IPV-HepB-Hib: 4.06 (3.04–5.42)μg/ml Monovalent PRP-OMPC: 2.46 (1.81–3.33)μg/ml	Not evaluated
Martinon-Torres, et.al. NCT04535037	2 m, 4 m, 12 m (2 + 1 schedule)	DTaP5-IPV-HepB-Hib DTaP3-IPV-HepB/Hib	At 5 m of age (post-dose 2): DTaP5-IPV-HepB-Hib: 11.3 (9.4–13.6)μg/ml DTaP3-IPV-HepB/Hib: 0.5 (0.4–0.6)μg/ml	At 13 m of age: DTaP5-IPV-HepB-Hib: 12.9 (10.8–15.6)μg/ml DTaP3-IPV-HepB/Hib: 12.0 (10.0–14.3)μg/ml
Rajan, et.al. ISRCTN85819697	2 m, 3 m, 4 m, 12 m (3 + 0 schedule)†	DTaP5-IPV-HepB-Hib DTaP3-IPV-HepB/Hib 4CMenB	At 5 m of age (post-dose 3): DTaP5-IPV-HepB-Hib: 20.34 (14.58–28.37)μg/ml DTaP3-IPV-HepB/Hib: 0.87 (0.66–1.16)μg/ml	At 13 m of age: DTaP5-IPV-HepB-Hib: 88.07 (66.38–116.85)μg/ml DTaP3-IPV-HepB/Hib: 23.22 (16.57–32.53)μg/ml
Guerra, et.al. NCT05289271	2 m, 4 m, 11-13 m (2 + 1 schedule)	DTaP5-IPV-HepB-Hib DTaP2-IPV-HepB-Hib	At 11-13 m of age (prior to toddler dose): DTaP5-IPV-HepB-Hib infant series: 1.25 (0.92–1.70)μg/ml DTaP2-IPV-HepB-Hib infant series: 0.11 (0.10–0.13)μg/ml	At 12-14 m of age: DTaP5-IPV-HepB-Hib infant series: 5.85 (4.28–8.00)μg/ml DTaP2-IPV-HepB-Hib infant series: 5.12 (3.88–6.76)μg/ml
Benfield, et.al. NCT04016714	3 m, 5 m, 12 m (2 + 1 schedule)	DTaP5-IPV-HepB-Hib‡ PCV15 PCV13	Not evaluated	At 13 m of age: 96.8% and 97.9% of participants with anti-PRP ≥.15 μg/ml

*Short term and long term immunogenicity thresholds for anti-PRP are ≥0.15 μg/mL and ≥1.0 μg/mL, respectively.

+Participants received 3 doses of DTaP5-IPV-HepB-Hib or 2 doses of monovalent PRP-OMPC (2-4 m) according to existing recommendations.

†Hib-MenC combination vaccine was given as the toddler dose.

‡Primary study objective was the assessment of PCVs; DTaP5-IPV-HepB-Hib was given as concomitant vaccination in both study arms.

Hib immunogenicity of DTaP5-IPV-HepB-Hib following the first dose

Jackson et al.⁴⁷ evaluated the immunogenicity of DTaP5-IPV-HepB-Hib after the first infant dose compared to PedVaxHIB® (monovalent PRP-OMPC) vaccine in AI/AN infants. Monovalent PRP-OMPC has a preferential recommendation in this vulnerable population in the U.S. due to superior anti-Hib responses after a single dose in very young infants. DTaP5-IPV-HepB-Hib contains a lower amount of Hib conjugate (3.0 µg PRP) compared to monovalent PRP-OMPC (7.5 µg PRP). The selected amount of PRP was based on the results of a Phase II study, in which the 3 μg formulation had similar immunogenicity to the 6 μg formulation, with a better tolerability profile.⁴⁸ Nonetheless, information about anti-PRP responses of DTaP5-IPV-HepB-Hib after the first infant dose was missing. Following the first infant dose at 2 months of age (immunogenicity measured at 3 months of age), anti-PRP geometric mean concentrations (GMCs) were 0.41 μg/ml in the DTaP5-IPV-HepB-Hib group and 0.39 μg/ml in the monovalent PRP-OMPC group, which met the pre-specified noninferiority criteria between the vaccines.⁴⁷ Furthermore, the proportions of participants with antibody levels exceeding the short-term protection threshold of ≥0.15 μg/ml were 75.7% for the DTaP5-IPV-HepB-Hib group and 71.2% for the monovalent PRP-OMPC group. These data resulted in DTap5-IPV-HepB-Hib also gaining a preferential recommendation by the Advisory Committee on Immunization Practices for use in all AI/AN infants in the U.S. to provide strong infant Hib immunogenicity while additionally simplifying infant vaccination regimens.¹⁹

Hib immunogenicity of DTaP5-IPV-HepB-Hib following a 2 + 1 schedule

In addition to the study from the DTaP5-IPV-HepB-Hib clinical program exploring Hib immunogenicity in a 2 + 1 vaccination regimen,⁴⁵ anti-PRP responses of DTaP5-IPV-HepB-Hib and DTaP3-IPV-HepB/Hib in a 2, 4, and 12 month vaccination schedule were again evaluated in a trial conducted in Germany, Italy, and Spain.⁴⁹ Primary objectives included demonstration of non-inferiority of DTaP3-IPV-HepB/Hib compared to DTaP5-IPV-HepB-Hib after the toddler dose, as assessed by anti-PRP GMCs and the proportion of participants with an anti-PRP concentration ≥5 µg/ml. Protection against colonization has been postulated to be correlated with anti-PRP antibody concentrations of ≥5 μg/ml.⁵⁰ If noninferiority objectives were met, additional primary objectives were to evaluate superiority of DTaP3-IPV-HepB/Hib to DTaP5-IPV-HepB-Hib for the same measures of immunogenicity following the toddler dose.

One month after the toddler dose, anti-PRP GMCs were similar, with the adjusted GMC ratio of DTaP3-IPV-HepB/Hib to DTaP5-IPV-HepB-Hib being 0.917. The second primary objective, to evaluate noninferiority of the proportion of participants who received DTaP3-IPV-HepB/Hib and reached anti-PRP antibody concentrations ≥5 μg/ml, was not met. Since the second criterion for non-inferiority of DTap3-IPV-HepB/Hib to DTaP5-IPV-HepB-Hib was not met, the condition for evaluation of primary objectives on superiority was also not met. One month after the primary series (at 5 months of age) anti-PRP IgG GMCs were approximately 20-fold higher in the DTaP5-IPV-HepB-Hib group (11.3 μg/ml) compared to the DTaP3-IPV-HepB/Hib group (0.5 μg/ml),⁴⁹ which further confirms the robust infant response elicited by the PRP-OMPC conjugate. Furthermore, the higher GMCs were sustained through the vulnerable infant period with pre-booster anti-PRP GMCs in the DTaP5-IPV-HepB-Hib arm at 1.9 μg/ml, in contrast to 0.2 μg/ml in the DTaP3-IPV-HepB/Hib arm.

Benfield et al.⁵¹ examined the co-administration of PCV15 with DTaP5-IPV-HepB-Hib in a 3, 5, and 12 month schedule. Anti-PRP IgG GMCs following the toddler dose were robust and, numerically, similar to responses observed following a 2, 4, and 11 month schedule in other studies.

Hib immunogenicity of DTaP5-IPV-HepB-Hib when co-administered with meningococcal B vaccine

There is a theoretical risk of carrier-induced epitopic suppression of the Hib responses to DTaP5-IPV-HepB-Hib when given concurrently with meningococcal B vaccine (4CMenB/Bexsero) due to the OMPC carrier being derived from N. meningitidis serogroup b. As a consequence, this could potentially lead to a cohort of infants with sub-optimal immune responses to the Hib antigen with a risk of a recurrence of a Hib outbreak like that seen in the UK from 1999–2003.^52,53 In order to explore this, Rajan, et al.⁵⁴ examined the administration of DTaP5-IPV-HepB-Hib or DTaP3-IPV-HepB/Hib given concomitantly with the 4CMenB vaccine according to the UK schedule. The primary immunogenicity endpoint was non-inferiority of DTaP5-IPV-HepB-Hib anti-PRP responses at 5 months (following three doses of the infant series). At 12 months of age, a booster dose of Hib/MenC combination vaccine was given. At 5 months, DTaP5-IPV-HepB-Hib recipients had anti-PRP GMCs more than 20-fold higher than the comparator group, and at 13 months GMCs were still approximately 5-fold higher. The immune response to 4CMenB was similar between the groups, and there was no observed difference in reactogenicity between the groups.⁵⁴ These data confirm that no carrier-induced suppression occurred; on the contrary, an apparent boost in anti-PRP responses was observed.

Hib immunogenicity of DTaP5-IPV-HepB-Hib in a mixed schedule To evaluate interchangeability of HV vaccines, Guerra, et al.⁵⁵ enrolled 11–13 month old children who had received a two-dose infant series of either DTaP2-IPV-HepB-Hib or DTaP5-IPV-HepB-Hib at 2 and 4 months of age as part of their routine immunizations. These children all subsequently received DTaP5-IPV-HepB-Hib at the toddler dose. Prior to the toddler vaccination, 87.3% of participants in the DTaP5-IPV-HepB-Hib group had anti-PRP IgG levels exceeding the short-term designated protection threshold of ≥0.15 μg/mL as compared to 27.2% of participants in the DTaP2-IPV-HepB-Hib group. The anti-PRP GMCs prior to toddler vaccination were 1.25 μg/ml in the DTaP5-IPV-HepB-Hib group and 0.11 μg/ml in the DTaP2-IPV-HepB-Hib group. Following toddler vaccination with DTaP5-IPV-HepB-Hib, anti-PRP antibody responses were comparable. Study results support the use of DTaP5-IPV-HepB-Hib in mixed regimens if needed, and further corroborate the higher anti-PRP responses generated by DTaP5-IPV-HepB-Hib after a two dose primary series.

Discussion

When examining recent surveillance of invasive disease from H. influenzae it seems that, despite effective infant vaccination programs leading to high coverage rates throughout Europe, cases of invasive Hib disease still occur, particularly in children under 5 years of age. There are several possible factors that may contribute, including vaccination schedule, vaccination coverage rates, vaccine failures, durability of vaccine-induced antibody levels, escape variants that render the vaccines less effective, and/or the Hib conjugate used for vaccination.

The 2 + 1 vaccination schedule has in the recent past been more widely adopted into NIPs in countries in Europe, and the question has arisen as to whether the resulting antibody levels to Hib after a two dose primary vaccination are sufficiently robust to protect infants during the period prior to receiving the booster/toddler dose.^39,56 As mentioned above, conflicting epidemiological trends have been observed in some European countries, especially in those utilizing a 2 + 1 schedule. The studies reviewed here highlight the unique characteristics of the Hib immune response, making it particularly suited to the 2 + 1 schedule due to earlier and higher anti-PRP responses elicited by the PRP-OMPC conjugate even after the rigorous two dose infant series. This is particularly important as the window of time between the last infant dose and toddler dose when antibody levels wane is a critical window of susceptibility in infants. The higher antibody level achieved with the PRP-OMPC conjugate after the infant series results in a higher proportion of infants retaining robust antibody levels through the first year of life prior to the toddler booster. Furthermore, similar immunogenicity is achieved one month following the toddler dose in 2 + 1 and 3 + 1 vaccination regimens.⁴⁴ These are all potential advantages to limit invasive Hib disease, particularly in infants and young children.

Other factors such as prematurity, underlying health conditions, immunological deficiencies, and differences in vaccination coverage rates, as well as timing of the booster dose must also be considered with these reports. Declining vaccination rates in recent years (with the COVID-19 pandemic as an additional complication) are another factor that may contribute to increased invasive Hib disease. However, vaccination rates remain well above 90% which suggests it is difficult to explain the observed differences in disease incidence with vaccination rates alone. While vaccine failures have been reported in invasive Hib cases,^36,38,39 there is insufficient data to determine whether the overall small number of cases have increased in recent years or are linked to a particular vaccination regimen. Data on nasopharyngeal Hib colonization could provide more insight in countries where an increase in cases has been noted. Prevention of colonization in infants may additionally benefit older adults through indirect protection. There are limited data on long-term durability of HV-induced antibodies other than hepatitis B antibodies.^57–59 Studies that have evaluated anti-PRP antibodies approximately 3 years after the toddler dose suggest sustained antibody levels, with more than 80% of participants above the long-term immunogenicity threshold of ≥1.0 μg/mL.^60–62 Finally, the development of a Hib escape variant is another possibility, although molecular typing studies suggest this is not the case.^36–38

Recently published studies discussed above help address important data gaps with DTaP5-IPV-HepB-Hib, such as post-dose 1 immunogenicity in high-risk infants and co-administration with meningococcal B vaccine. These findings reinforce the value of DTaP5-IPV-HepB-Hib in infant vaccination schedules.

Conclusion

The World Health Organization visionary goal ‘towards a world free of meningitis’ in their 2030 road map requires, first and foremost, addressing health equity and vaccine infrastructure in regions with high endemicity, but also maintaining adequate robust meningitis prevention strategies such as vaccination in countries with effective programs.⁶³ Effective vaccination programs across Europe have made invasive Hib disease rare, and even in the above reports the overall incidence remains low. Observed increases in invasive Hib disease may require a critical analysis of available data and adjustments to public health strategies to maintain low disease incidence in infants and children. The recently published studies discussed here demonstrate the PRP-OMPC conjugate is immunogenic in a 2 + 1 vaccination schedule and maintains the characteristic of strong infant PRP responses when used in DTaP5-IPV-HepB-Hib.

Biography

Marissa Wilck is a Senior Principal Scientist of clinical research at Merck & Co., Inc., Rahway, NJ, USA

Funding Statement

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD).

Authorship contributions

M-K.T., T.M., T.J.C., R.F., D.R.J., and M.W. substantially contributed to the conception, design, or planning of the study, the acquisition or analysis of the data, drafting of the manuscript, and/or the interpretation of the results. All authors critically reviewed or revised the manuscript for important intellectual content and approved the final version.

Disclosure statement

M-K.T. has no potential conflicts of interest to report. T.M. is an employee of MCM Vaccine and may hold stock in Merck & Co., Inc., Rahway, New Jersey, USA. T.J.C., R.F., and M.W. are employees of MSD and may hold stock in Merck & Co., Inc., Rahway, New Jersey, USA. D.R.J. is a former employee of Sanofi.

Data sharing

The data sharing policy, including restrictions, of MSD, is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the Engage Zone site or via e-mail to the Data Access mailbox.

Ethical approvals

Ethical approvals relevant to human participant trials were not needed for this manuscript.