Effectiveness of 2 + 1 PCV7 vaccination schedules in children under 2 years: A meta-analysis of impact studies

doi:10.1016/j.vaccine.2013.10.042

Vaccine

Volume 31, Issue 50, 5 December 2013, Pages 5948-5952

https://doi.org/10.1016/j.vaccine.2013.10.042 Get rights and content

Highlights

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Meta-analysis of IPD reduction in children <2 year suggested high effectiveness of the 2 + 1 vaccine schedule.
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Beyond reported vaccination rates we identified two further determinants for heterogeneity; matching of periods of vaccination rates and case ascertainment; time gap between onset of vaccination programme and case ascertainment.
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IRR of 98% may be identified with vaccination rates >80% and optimal study design.

Abstract

Although a case control study suggested high effectiveness of the 2 + 1 PCV-7 vaccination, schedule against invasive pneumococcal disease (IPD) in children the results of impact studies in, different countries yield considerable differences in the magnitude of the effects. A systematic, literature review was conducted to identify all relevant studies on IPD incidence reduction after onset, of PCV7 vaccination programmes in children younger than 2 years of age given in the 2 + 1 schedule. The incidence rate ratio between IPI incidences for vaccine serotypes before and after beginning of the, vaccination programme was calculated for each study. Heterogeneity was assessed and attempts to, identify causes for heterogeneity were made. In the literature search 4 studies which fulfilled inclusion, criteria were identified. The summary estimates yielded an IRR 0.10 [0.04; 0.30] suggesting a 90%, incidence reduction. Heterogeneity was high with I² = 93%. Heterogeneity might be explained by, differences in vaccination rates, the way vaccination rates were assessed, matching of the periods of, vaccination and case ascertainment, time between onset of the vaccination programme and onset of, case ascertainment during the vaccination period and the length of the observation period after onset, of the vaccination programme. A study which started 3 years after onset of the vaccination programme, with vaccination rates ≥80% throughout the ascertainment period of the incidence rates reported a, 98% reduction in the incidence rates. A meta-analysis on IRR studies on reductions of the IPD, incidence in children <2 years of age suggested high effectiveness of the 2 + 1 vaccination schedule for PCV 7.

Introduction

Conjugate pneumococcal vaccines were developed to allow for vaccinating young children who constitute an important risk group for invasive pneumococcal disease (IPD). The clinical efficacy of the 7-valent Pneumococcal conjugate vaccine (PCV7) was demonstrated for a 3 + 1 schedule in a randomized controlled trail (RCT) in California [1] which was a prerequisite for licensing. A shortage in vaccine supply necessitated reduced vaccinations with PCV7 resulting in a temporary recommendation for a 3 + 0 or 2 + 0 schedule; some children received a 2 + 1 schedule because when they came for the third primary dose the clinic would be out of vaccination so the child got ‘caught up’ at the 12-month visit. Thus allowed for a case control study in the US between 2001 and 2004 [2], [3] to compare the vaccine effectiveness (VE) of the reduced (2 + 1) and recommended vaccination schedule (3 + 1). The VE of both schedules proved almost identical. [3]. Two recent meta-analyses showed similar antibody titres for most serotypes with both vaccination schedules [4], [5] measured before as well as after the receipt of a booster dose.

Despite these finding only few countries which already had 3 + 1 vaccination programmes in place switched to a 2 + 1 vaccination schedule (e.g. Belgium [6]). Some but not all countries initiating pneumococcal conjugate vaccination recommendations in 2006 or later adopted a 2 + 1 doses vaccination regime (e.g. Norway and the UK [7], [8], [9]) while others introduced a 3 + 1 (e.g. The Netherlands [10], [11] and Germany [12]). A reduced vaccine schedule spares the children the inconvenience of an additional vaccination and increases cost effectiveness [13], [14].

A common approach to assess the impact of vaccinations in populations is by estimating the incidence reduction ratio (IRR) (difference of incidence before by incidence after the introduction of vaccination) in impact studies. Comparison of the impact on all IPD irrespective of the serotype needs to take account of multiple determinants such as the regional serotype distribution before vaccine introduction and replacement. With confinement of the analyses on the impact on vaccine serotypes a more valid estimate appears possible. Surprisingly the impact estimates varied considerably between countries – between 0.02 [8] and 0.29 [9] despite similar vaccination rates.

We therefore performed a systematic review to assess the impact of 2 + 1 pneumococcal vaccination schedules on the incidence reduction in IPD cases related to vaccine serotypes for children younger than 2 years in different countries. What are the causes for differences? Is a meta-analysis to provide a best summary estimate possible?

Section snippets

Methods

The main outcome is the vaccine serotype specific incidence reduction (rate ratio) for IPD in children younger than 2 years after PCV7 introduction. We confined this systematic review because there are virtually no populations where PCV 10 and PCV 13 were introduced without prior use of PCV7. Therefore the impact with reference to non vaccination can only be assessed for PCV7 studies.

Results

The flow diagram shows the results of literature search yielding a total of 4987 articles after exclusion of duplicates. After checking titles and abstracts 161 articles remained for full text scan, of these 4 studies using a 2 + 1 vaccination schedule fulfilled inclusion criteria (Fig. 1).

The included 4 studies reported full information on incidence rates and vaccine serotypes before and after vaccine introduction. If no information about the vaccination rates were reported in the studies we

Main findings

The results of our meta-analysis suggest an overall 90% reduction in IPD rates for vaccine serotypes with the 2 + 1 vaccine scheme. The considerable heterogeneity between studies, which could not be explained by vaccination coverage, was related to matching of the observation period of incidence ascertainment and the time period pertaining to the reported vaccination coverage and to the time gap between the onset of the vaccination programme and ascertainment of IPD cases. With ascertainment of

Conclusions

The overall summary estimate for the impact of 2 + 1 schedules on the reduction of the incidence of vaccine serotypes in children younger 2 years in different countries suggested a high effectiveness of the 2 + 1 schedule. With confinement to studies initiated at least 3 years after onset of the vaccination programme with vaccination rates >80% are maintained throughout the ascertainment period of the incidence rates the impact on incidence reduction may be as high and potentially even higher than

Acknowledgement

Part of this work result from the MD thesis of K.K. at the medical faculty of the Ludwig-Maximilians-University of Munich (in preparation).
Conflict of interest

None.

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Cited by (10)

Effect of different schedules of ten-valent pneumococcal conjugate vaccine on pneumococcal carriage in Vietnamese infants: results from a randomised controlled trial
2023, The Lancet Regional Health - Western Pacific
Citation Excerpt :
Data directly comparing different PCV schedules are crucial to show the comparative direct and indirect effects that can be expected, generating evidence to support decisions regarding the introduction and ongoing use of infant PCV both in Vietnam and elsewhere. Pneumococcal conjugate vaccines (PCVs) are an important measure in preventing pneumococcal disease through direct protection as well as through indirect (herd) protection facilitated by reduced nasopharyngeal carriage of vaccine-types in a population.1,2 Infant PCV schedules still garner much attention as pneumococcal infections remain a major cause of morbidity and mortality in children under 5 years of age globally.3
WHO recommends a three-dose infant pneumococcal conjugate vaccine (PCV) schedule administered as a two-dose primary series with booster (2 + 1) or a three-dose primary series (3 + 0). Data on carriage impacts of these and further reduced PCV schedules are needed to inform PCV strategies. Here we evaluate the efficacy against carriage of four different PCV10 schedules.
Participants within an open-label, randomised controlled trial in Ho Chi Minh City, Vietnam, were allocated to receive PCV10 in a 3 + 1 (2,3,4,9 months, n = 152), 3 + 0 (2,3,4 months, n = 149), 2 + 1 (2,4,9.5 months, n = 250) or novel two-dose (2,6 months, n = 202) schedule, or no infant doses of PCV (two control groups, n = 197 and n = 199). Nasopharyngeal swabs collected between 2 and 24 months were analysed (blinded) for pneumococcal carriage and serotypes. Trial registration: ClinicalTrials.gov NCT01953510.
Pneumococcal carriage prevalence was low (10.6–14.1% for vaccine-type (VT) at 12–24 months in unvaccinated controls). All four PCV10 schedules reduced VT carriage compared with controls (the 2 + 1 schedule at 12, 18, and 24 months; the 3 + 1 and two-dose schedules at 18 months; and the 3 + 0 schedule at 24 months), with maximum reductions of 40.1%–64.5%. There were no differences in VT carriage prevalence at 6 or 9 months comparing three-dose and two-dose primary series, and no differences at 12, 18, or 24 months when comparing schedules with and without a booster dose.
In Vietnamese children with a relatively low pneumococcal carriage prevalence, 3 + 1, 2 + 1, 3 + 0 and two-dose PCV10 schedules were effective in reducing VT carriage. There were no discernible differences in the effect on carriage of the WHO-recommended 2 + 1 and 3 + 0 schedules during the first two years of life. Together with the previously reported immunogenicity data, this trial suggests that a range of PCV schedules are likely to generate significant direct and indirect protection.
NHMRC, BMGF
Immunogenicity of alternative ten-valent pneumococcal conjugate vaccine schedules in infants in Ho Chi Minh City, Vietnam: results from a single-blind, parallel-group, open-label, randomised, controlled trial
2021, The Lancet Infectious Diseases
Citation Excerpt :
Pneumococcal infections cause invasive diseases (eg, meningitis and sepsis) and mucosal diseases (eg, pneumonia and otitis media), and are a major cause of morbidity and mortality in children younger than 5 years globally.1 Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive pneumococcal disease2–5 and providing indirect herd protection through reduced nasopharyngeal carriage.6 Two PCVs are currently in use, a ten-valent PCV (PCV10; Synflorix, GSK Vaccines, Rixensart, Belgium) containing serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, and a 13-valent PCV (PCV13; Prevenar, Pfizer, Philadelphia, PA, USA) that contains the ten serotypes in PCV10 plus serotypes 3, 6A, and 19A.
Data are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam.
In this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9·5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3–18 months depending on group allocation, within 27–43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0·35 μg/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual.
Between Sept 30, 2013, and Jan 9, 2015, 1201 infants were enrolled and randomly assigned to group A (n=152), group B (n=149), group C (n=250), group D (n=202), or groups E (n=251) and F (n=197). In groups A–D, 388 (52%) of 753 participants were female and 365 (48%) were male. 286 (95%) participants in groups A and B combined (three-dose primary series) and 237 (95%) in group C (two-dose primary series) completed the primary vaccination series and had blood samples taken within the specified time window at age 5 months (per-protocol population). At this timepoint, a two-dose primary series was non-inferior to a three-dose primary series for eight of ten vaccine serotypes; exceptions were 6B (84·6% [95% CI 79·9–88·6] of infants had protective IgG concentrations after three doses [groups A and B combined] vs 76·8% [70·9–82·0] of infants after two doses [group C]; risk difference 7·8% [90% CI 2·1–13·6]) and 23F (90·6% [95% CI 86·6–93·7] vs 77·6% [71·8–82·2]; 12·9% [90% CI 7·7–18·3]). Two doses at ages 2 and 6 months produced higher antibody levels than two doses at ages 2 and 4 months for all serotypes except 5 and 7F.
A two-dose primary vaccination series was non-inferior to a three-dose primary vaccination series while two doses given with a wider interval between doses increased immunogenicity. The use of a two-dose primary vaccination schedule using a wider interval could be considered in LMIC settings to extend protection in the second year of life.
Australian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation.
A bibliometric analysis of systematic reviews on vaccines and immunisation
2018, Vaccine
Citation Excerpt :
This not only leads to gaps in knowledge if particular questions are neglected, but also to duplication and overlap. Therefore, many NITAGs commission reviews to inform them, which leads to duplication [6–11]. At present, there is no common understanding of what vaccine-relevant systematic reviews have, or have not, been conducted.
SYSVAC is an online bibliographic database of systematic reviews and systematic review protocols on vaccines and immunisation compiled by the London School of Hygiene & Tropical Medicine and hosted by the World Health Organization (WHO) through their National Immunization Technical Advisory Groups (NITAG) resource centre (www.nitag-resource.org). Here the development of the database and a bibliometric review of its content is presented, describing trends in the publication of policy-relevant systematic reviews on vaccines and immunisation from 2008 to 2016.
Searches were conducted in seven scientific databases according to a standardized search protocol, initially in 2014 with the most recent update in January 2017. Abstracts and titles were screened according to specific inclusion criteria. All included publications were coded into relevant categories based on a standardized protocol and subsequently analysed to look at trends in time, topic, area of focus, population and geographic location.
After screening for inclusion criteria, 1285 systematic reviews were included in the database. While in 2008 there were only 34 systematic reviews on a vaccine-related topic, this increased to 322 in 2016. The most frequent pathogens/diseases studied were influenza, human papillomavirus and pneumococcus. There were several areas of duplication and overlap.
As more systematic reviews are published it becomes increasingly time-consuming for decision-makers to identify relevant information among the ever-increasing volume available. The risk of duplication also increases, particularly given the current lack of coordination of systematic reviews on vaccine-related questions, both in terms of their commissioning and their execution. The SYSVAC database offers an accessible catalogue of vaccine-relevant systematic reviews with, where possible access or a link to the full-text.
SYSVAC provides a freely searchable platform to identify existing vaccine-policy-relevant systematic reviews. Systematic reviews will need to be assessed adequately for each specific question and quality.
Comparison of two-dose priming plus 9-month booster with a standard three-dose priming schedule for a ten-valent pneumococcal conjugate vaccine in Nepalese infants: A randomised, controlled, open-label, non-inferiority trial
2015, The Lancet Infectious Diseases
Citation Excerpt :
First, we examined a broad range of correlates of protection but could not directly assess the efficacy of PCV10 against disease. However, a recent meta-analysis estimated a 90% reduction in disease incidence with a 2+1 schedule using the lower-valency PCV7.18 Second, carriage was only measured at a single timepoint, whereas longitudinal measurement in a larger population might have provided greater insight into prevalent serotypes at alternate stages of infancy or childhood and allowed serotype-specific comparison between study groups.
Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood.
We did an open-label, randomised, parallel group, controlled trial in healthy infants aged 40–60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2–4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0·2 μg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0·2 μg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0·2 μg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0·2 μg/mL for PCV10 serotypes at age 2–4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232.
Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0·2 μg/mL were 99·0% (95% CI 94·2–100·0) for serotype 1, 100% (96·2–100·0) for serotype 5, and 97·9% (92·5–99·7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0·2 μg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2–4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 18C.
Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre-implementation and post-implementation surveillance is being done by a GAVI Alliance funded study.
This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium.
Vaccination against hepatitis B. Impact of vaccination programmes after 20 years of use in Spain. is it time for a change?
2015, Enfermedades Infecciosas y Microbiologia Clinica
La tasa de incidencia más alta de hepatitis B (HB) en España se detecta en los adultos entre 20 y 54 años, mientras que la incidencia de casos en menores de un año es casi nula. La baja prevalencia de HB en los menores de un año se debe principalmente al éxito de las estrategias de cribado gestacional para la detección de gestantes HBsAg(+) y a las campañas de vacunación durante la infancia. Actualmente en España la última dosis de la vacuna frente a la HB en el calendario de vacunación infantil es a los 6 meses de edad, si bien hay estudios que demuestran que retrasar la edad de la administración de la última dosis y aumentar el tiempo entre las dosis pueden mejorar la memoria inmunológica ofreciendo una mayor protección frente al virus en la edad adulta. Se revisa el impacto de la vacunación frente a la HB en España y se comentan otras estrategias posibles de vacunación en nuestro medio, ampliando el intervalo entre dosis y la administración de la última dosis en el segundo año de la vida, adaptando la estrategia vigente en España al actual contexto epidemiológico con el fin de disminuir la prevalencia en la edad adulta.
The highest incidence rate of hepatitis B (HB) in Spain is detected in adults between 20 and 54 years old, whereas the incidence in children under 1 year old is almost nil. The low prevalence of HB in children under 1 year is mainly due to the success of gestational screening strategies for the detection of HBsAg(+) in pregnant women, and vaccination campaigns during childhood. Currently, in Spain, the last dose of the HB included in the national childhood immunization program is administered at 6 months of age, although some studies show that delaying the age of the administration of the last dose of HB vaccine and increasing the time between doses, may improve immune memory by offering greater protection against this virus in the adulthood. In this article, the impact of HB vaccination in Spain is reviewed, and other potential vaccination strategies in our environment are discussed, such as extending the interval between doses, and administering the last dose in the second year of life, adapting the valid strategy in Spain to the current epidemiological context in order to reduce the prevalence of HB in adulthood.
Geographic variation in pneumococcal vaccine efficacy estimated from dynamic modeling of epidemiological data post-PCV7
2017, Scientific Reports

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Effectiveness of 2 + 1 PCV7 vaccination schedules in children under 2 years: A meta-analysis of impact studies

Highlights

Abstract

Introduction

Section snippets

Methods

Results

Main findings

Conclusions

Acknowledgement

Lancet

Vaccine

Vaccine

Vaccine

Lancet Infect Dis

Vaccine

Vaccine

Control Clin Trials

Vaccine

Vaccine

Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine

Pediatr Infect Dis J