Added value of the measles-rubella supplementary immunization activity in reaching unvaccinated and under-vaccinated children, a cross-sectional study in five Indian districts, 2018-20.

INTRODUCTION: Supplementary immunization activities (SIAs) aim to interrupt measles transmission by reaching susceptible children, including children who have not received the recommended two routine doses of MCV before the SIA. However, both strategies may miss the same children if vaccine doses are highly correlated. How well SIAs reach children missed by routine immunization is a key metric in assessing the added value of SIAs. METHODS: Children aged 9 months to younger than 5 years were enrolled in cross-sectional household serosurveys conducted in five districts in India following the 2017-2019 measles-rubella (MR) SIA. History of measles containing vaccine (MCV) through routine services or SIA was obtained from documents and verbal recall. Receipt of a first or second MCV dose during the SIA was categorized as "added value" of the SIA in reaching un- and under-vaccinated children. RESULTS: A total of 1,675 children were enrolled in these post-SIA surveys. The percentage of children receiving a 1st or 2nd dose through the SIA ranged from 12.8% in Thiruvananthapuram District to 48.6% in Dibrugarh District. Although the number of zero-dose children prior to the SIA was small in most sites, the proportion reached by the SIA ranged from 45.8% in Thiruvananthapuram District to 94.9% in Dibrugarh District. Fewer than 7% of children remained measles zero-dose after the MR SIA (range: 1.1-6.4%) compared to up to 28% before the SIA (range: 7.3-28.1%). DISCUSSION: We demonstrated the MR SIA provided considerable added value in terms of measles vaccination coverage, although there was variability across districts due to differences in routine and SIA coverage, and which children were reached by the SIA. Metrics evaluating the added value of an SIA can help to inform the design of vaccination strategies to better reach zero-dose or undervaccinated children.

Vaccination strategies for measles control and elimination: time to strengthen local initiatives.

BACKGROUND: Through a combination of strong routine immunization (RI), strategic supplemental immunization activities (SIA) and robust surveillance, numerous countries have been able to approach or achieve measles elimination. The fragility of these achievements has been shown, however, by the resurgence of measles since 2016. We describe trends in routine measles vaccine coverage at national and district level, SIA performance and demographic changes in the three regions with the highest measles burden. FINDINGS: WHO-UNICEF estimates of immunization coverage show that global coverage of the first dose of measles vaccine has stabilized at 85% from 2015 to 19. In 2000, 17 countries in the WHO African and Eastern Mediterranean regions had measles vaccine coverage below 50%, and although all increased coverage by 2019, at a median of 60%, it remained far below levels needed for elimination. Geospatial estimates show many low coverage districts across Africa and much of the Eastern Mediterranean and southeast Asian regions. A large proportion of children unvaccinated for MCV live in conflict-affected areas with remote rural areas and some urban areas also at risk. Countries with low RI coverage use SIAs frequently, yet the ideal timing and target age range for SIAs vary within countries, and the impact of SIAs has often been mitigated by delays or disruptions. SIAs have not been sufficient to achieve or sustain measles elimination in the countries with weakest routine systems. Demographic changes also affect measles transmission, and their variation between and within countries should be incorporated into strategic planning. CONCLUSIONS: Rebuilding services after the COVID-19 pandemic provides a need and an opportunity to increase community engagement in planning and monitoring services. A broader suite of interventions is needed beyond SIAs. Improved methods for tracking coverage at the individual and community level are needed together with enhanced surveillance. Decision-making needs to be decentralized to develop locally-driven, sustainable strategies for measles control and elimination.

Using models to shape measles control and elimination strategies in low- and middle-income countries: A review of recent applications.

After many decades of vaccination, measles epidemiology varies greatly between and within countries. National immunization programs are therefore encouraged to conduct regular situation analyses and to leverage models to adapt interventions to local needs. Here, we review applications of models to develop locally tailored interventions to support control and elimination efforts. In general, statistical and semi-mechanistic transmission models can be used to synthesize information from vaccination coverage, measles incidence, demographic, and/or serological data, offering a means to estimate the spatial and age-specific distribution of measles susceptibility. These estimates complete the picture provided by vaccination coverage alone, by accounting for natural immunity. Dynamic transmission models can then be used to evaluate the relative impact of candidate interventions for measles control and elimination and the expected future epidemiology. In most countries, models predict substantial numbers of susceptible individuals outside the age range of routine vaccination, which affects outbreak risk and necessitates additional intervention to achieve elimination. More effective use of models to inform both vaccination program planning and evaluation requires the development of training to enhance broader understanding of models and where feasible, building capacity for modelling in-country, pipelines for rapid evaluation of model predictions using surveillance data, and clear protocols for incorporating model results into decision-making.

The effect of distance on observed mortality, childhood pneumonia and vaccine efficacy in rural Gambia.

We investigated whether straight-line distance from residential compounds to healthcare facilities influenced mortality, the incidence of pneumonia and vaccine efficacy against pneumonia in rural Gambia. Clinical surveillance for pneumonia was conducted on 6938 children living in the catchment areas of the two largest healthcare facilities. Deaths were monitored by three-monthly home visits. Children living >5 km from the two largest healthcare facilities had a 2·78 [95% confidence interval (CI) 1·74-4·43] times higher risk of all-cause mortality compared to children living within 2 km of these facilities. The observed rate of clinical and radiological pneumonia was lower in children living >5 km from these facilities compared to those living within 2 km [rate ratios 0·65 (95% CI 0·57-0·73) and 0·74 (95% CI 0·55-0·98), respectively]. There was no association between distance and estimated pneumococcal vaccine efficacy. Geographical access to healthcare services is an important determinant of survival and pneumonia in children in rural Gambia.

Immunogenicity and serotype-specific efficacy of a 9-valent pneumococcal conjugate vaccine (PCV-9) determined during an efficacy trial in The Gambia.

This study aimed to determine the immunogenicity of a 9-valent pneumococcal conjugate vaccine (PCV-9) in a subgroup of Gambian children enrolled in a large vaccine efficacy trial. To place the antibody results in context, in this paper we also report previously unpublished data on serotype-specific clinical vaccine efficacy from the main trial. In the sub-study, a single 2-4 ml venous blood specimen was collected from 212 Gambian children 4-6 weeks after the administration of a third dose of PCV-9 or placebo. IgG antibodies to pneumococcal serotype 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F polysaccharides were measured by ELISA. The proportions of infants with antibody concentrations above 0.2, 0.35 and 1.0 microg/ml, and the geometric mean concentrations (GMCs) of anti-pneumococcal polysaccharide antibodies were substantially higher for each serotype in children who received three doses of PCV-9 than those in the placebo group. Among PCV-9 recipients, GMCs ranged between 2.61 and 11.09 microg/ml with the highest being against serotype 14 and the lowest against 9V polysaccharide. The estimated overall protective antibody level for all nine serotypes, based on the vaccine efficacy against vaccine-type invasive pneumococcal disease (IPD) of 77% (95% CI: 51, 90) observed in the trial, was 2.3 microg/ml (95% CI: 1.0, 5.0). The PCV-9 studied was immunogenic in a Gambian population where it was also found to be efficacious.

Human papillomavirus and HPV vaccines: a review.

Cervical cancer, the most common cancer affecting women in developing countries, is caused by persistent infection with "high-risk" genotypes of human papillomaviruses (HPV). The most common oncogenic HPV genotypes are 16 and 18, causing approximately 70% of all cervical cancers. Types 6 and 11 do not contribute to the incidence of high-grade dysplasias (precancerous lesions) or cervical cancer, but do cause laryngeal papillomas and most genital warts. HPV is highly transmissible, with peak incidence soon after the onset of sexual activity. A quadrivalent (types 6, 11, 16 and 18) HPV vaccine has recently been licensed in several countries following the determination that it has an acceptable benefit/risk profile. In large phase III trials, the vaccine prevented 100% of moderate and severe precancerous cervical lesions associated with types 16 or 18 among women with no previous infection with these types. A bivalent (types 16 and 18) vaccine has also undergone extensive evaluation and been licensed in at least one country. Both vaccines are prepared from non-infectious, DNA-free virus-like particles produced by recombinant technology and combined with an adjuvant. With three doses administered, they induce high levels of serum antibodies in virtually all vaccinated individuals. In women who have no evidence of past or current infection with the HPV genotypes in the vaccine, both vaccines show > 90% protection against persistent HPV infection for up to 5 years after vaccination, which is the longest reported follow-up so far. Vaccinating at an age before females are exposed to HPV would have the greatest impact. Since HPV vaccines do not eliminate the risk of cervical cancer, cervical screening will still be required to minimize cancer incidence. Tiered pricing for HPV vaccines, innovative financing mechanisms and multidisciplinary partnerships will be essential in order for the vaccines to reach populations in greatest need.

Serological and molecular epidemiology of measles virus outbreaks reported in Ethiopia during 2000-2004.

Twenty-eight outbreaks in six regions and two major cities in Ethiopia from 2000 to 2004 were investigated, with the collection of 207 venous blood and/or oral fluid samples. Measles diagnosis was confirmed by detection of measles-specific IgM and/or detection of measles virus by polymerase chain reaction (PCR). Of 176 suspected cases tested for specific measles IgM, 142 (81%) were IgM positive. Suspected cases in vaccinated children were much less likely to be laboratory confirmed than in unvaccinated children (42% vs. 83%, P < 0.0001). Of 197 samples analyzed by RT-PCR measles virus genome was detected in 84 (43%). A total of 58 wild-type measles viruses were characterized by nucleic acid sequence analysis of the nucleoprotein (N) and hemagglutinin (H) genes. Two recognized genotypes (D4 and B3) were identified. Each outbreak comprised only a single genotype and outbreaks of each genotype tended to occur in distinct geographical locations. B3 was first observed in 2002, and has now been the cause of three documented outbreaks near to the border of Sudan. D4 genotype was previously observed in an outbreak in 1999 and occurs in more diverse locations throughout the country. These data yield insights into geographical and age-related sources of continued transmission. Refinement of measles control measures might include targeting older age groups (5-14 years) and strengthening routine immunization particularly where importation of cases is a concern.

Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. METHODS: We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. FINDINGS: 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. INTERPRETATION: In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

Vaccines for neonatal viral infections: hepatitis B vaccine.

In many parts of the world, intervention in the neonatal period is required for prevention of hepatitis B virus infection and its consequences.

Seroepidemiology of hepatitis B virus in Addis Ababa, Ethiopia: transmission patterns and vaccine control.

A community-based seroepidemiological survey of Addis Ababa, Ethiopia was conducted in 1994 to inform on the transmission dynamics and control of hepatitis B virus (HBV) infection. Venous blood from 4736 individuals under 50 years of age from 1262 households, selected using stratified cluster-sampling, was screened for HBV markers using commercial ELISAs. HBsAg prevalence was 7% (95 % CI 6-8), higher in males (9%; 7-10) than females (5%; 4-6). HBeAg prevalence in HBsAg positives was 23% (18-29), and less than 1% of women of childbearing age were HBeAg positive. Overall HBV seroprevalence (any marker), rose steadily with age to over 70% in 40-49 year olds, indicating significant childhood and adult transmission. Estimated instantaneous incidence was 3-4/100 susceptibles/year, higher in males than females in 0-4 year olds, and peaking in early childhood and young adults. The age at which 50% had evidence of infection was around 20 years, and the herd immunity threshold is approximated at 63-77%. Addis Ababa is of intermediate-high HBV endemicity, with negligible perinatal transmission. Our main findings are the identification of a significant difference between males and females in the age-acquisition of HBV infection, and marked differences between age groups in HBV incidence rates. These results should target future research studies of underlying risk factors. Furthermore, we generate a crude estimate of the level of coverage of HBV vaccine that would be required to eliminate the virus from the study population.

Seroepidemiology of measles in Addis Ababa, Ethiopia: implications for control through vaccination.

We undertook a representative survey of measles antibodies in Addis Ababa, Ethiopia 1994, to characterize immunity and transmission. Specific-antibody levels (IU/l) were determined by ELISA for 4654 sera from individuals aged 0-49 years (1805 < 15 years) collected by stratified household-cluster sampling. The proportion seronegative (< 100 IU/l) was 20% (95% CI: 16-25) in children 9-59 months old, declining to 9% (7-12) in 5-9 year olds, 5% (4-7) in 10-14 year olds, and < 1% in adults. The proportion of children (< 15 years old) with low-level antibody (100-255 IU/l) was 8% (7-10). Vaccination and an absence of a history of measles illness were strongly associated with low-level antibody. History of measles vaccination in 9 months to 14-year-old children was approximately 80%. We estimate a primary vaccine failure rate of 21% (12-34) and continued high measles incidence of 22 per 100 susceptibles (19-24) per annum. Our data support the introduction of campaign vaccination in the city in 1998, although higher routine vaccine coverage is required to sustain the impact. The implications of a high prevalence of low-level antibody are discussed.

The predicted impact of private sector MMR vaccination on the burden of Congenital Rubella Syndrome.

In many developing countries, Measles-Mumps-Rubella (MMR) vaccine is available through the private but not the public sectors, and there is no systematic rubella vaccination among adult women. In this paper, we extend previous modeling studies to demonstrate that in developing countries with a medium-high force of infection (200-400/1000 per year), current levels of private sector MMR coverage (<60%) would lead to increases in the incidence of Congenital Rubella Syndrome (CRS) both among unvaccinated individuals and the general population even when mixing between vaccinated and unvaccinated individuals is fairly minimal. Our findings highlight the need for countries to establish surveillance of trends in susceptibility to rubella and CRS incidence and perhaps introduce rubella vaccination among women of child-bearing age.

Measles trends and vaccine effectiveness in Nairobi, Kenya.

OBJECTIVES: To determine morbidity and mortality from measles and to estimate measles vaccine effectiveness among children hospitalised with measles in two hospitals in Nairobi. DESIGN: A review of hospital records (index cards). SETTING: Kenyatta National Hospital and Mbagathi District Hospitals covering the years 1996-2000. METHOD: A review of index cards for measles morbility and mortality was undertaken in the two hospitals. Measles data at the Kenya Expanded Programme on Immunisation covering both hospitals was analysed for vaccine effectiveness. RESULTS: The incidence of measles was unusually high in 1998 between July and November (monthly range 130-305), reflecting on the occurrence of an outbreak at that time. There was no definite monthly incidence trend of measles in 1996,1997, 1999 and 2000. The median age of cases was 13 months (range 0-420 months) for Kenyatta hospital and 18 months (range 1-336 months) for Mbagathi Hospital. Significantly, 29.8% of all cases were aged below nine months when routine immunisation for measles had not begun. The median number of days spent in hospital were five days (range 0-87 days) for Kenyatta and four days (range 1-13 days) for Mbagathi. The overall case fatality rate was 5.6% and was similar for both males and females. The overall measles vaccine effectiveness among measles cases admitted to Kenyatta and Mbagathi Hospitals was 84.1%. CONCLUSION: The case admissions in Kenyatta and Mbagathi Hospitals suggest measles was prevalent in Nairobi over the latter half decade of the 1990's. Apart from 1998 when there was an outbreak, the seasonality of measles was dampened. The 1998 outbreak suggests a build up of susceptible children the majority of whom were born in the last quarter of 1996. The high mortality may have had to do with the majority of cases presenting late when symptoms were already complicated and severe.

Measles virus strains circulating in Ethiopia in 1998-1999: molecular characterisation using oral fluid samples and identification of a new genotype.

A measles outbreak in December 1998 in Bedelle (vaccine coverage <40%) and two sporadic cases in Addis Ababa, Ethiopia, were investigated. Paired serum and oral fluid samples were collected 2-8 days after the onset of symptoms. A total of 53 of 55 outbreak cases and both sporadic cases were positive for serum measles virus-specific IgM. Oral fluid measles-specific IgM was positive in 71% of cases collected up to 5 days after onset and in 90% collected at 6-8 days. By contrast, 100% of oral fluid samples were positive for measles virus RNA by RT-PCR, suggesting that early collection of samples favoured the detection of measles virus RNA by RT-PCR. The measles virus strain in the outbreak was identified as genotype D4. One strain from a sporadic case was also genotype D4; the strain from the other sporadic case was assigned to clade D but was distinct. The degree of divergence from recognised clade D strains suggested that, together with three strains from the United Kingdom, it represents an additional genotype of clade D (GenBank accession numbers AF280800-280807).

Has oral fluid the potential to replace serum for the evaluation of population immunity levels? A study of measles, rubella and hepatitis B in rural Ethiopia.

OBJECTIVE: To assess the suitability of using oral-fluid samples for determining the prevalence of immunity to vaccine-preventable infections. METHODS: Paired blood and oral-fluid samples were obtained from 853 individuals of all ages from a rural Ethiopian community. Oral fluid around the gums was screened for measles- and rubella-specific antibodies using enhanced IgG antibody capture (GAC) enzyme-linked immunosorbent assays (ELISAs), and for anti-HBc antibodies using a prototype GACELISA. IgG antibodies in serum to measles, rubella and HBc were determined using commercial ELISAs. FINDINGS: Relative to serum, oral fluid assay sensitivity and specificity were as follows: 98% and 87% for measles, 79% and 90% for rubella, and 43% and 87% for anti-HBc. These assay characteristics yielded population prevalence estimates from oral fluid with a precision equal to that of serum for measles (all ages) and rubella (ages < 20 years). CONCLUSION: Our results suggest that oral fluid could have the potential to replace serum in IgG antibody prevalence surveys. Further progress requires assessment of variation in assay performance between populations as well as the availability of standardized, easy to use assays.

Immune modulation after measles vaccination of 6-9 months old Bangladeshi infants.

Measles still causes high mortality in children younger than 1 year of age. Administration of high titre measles vaccines before 7 months of age led to increased overall mortality, raising questions as to the immunological effects of measles vaccine in young infants. We investigated the immune response to standard titre vaccines given to children in Bangladesh in a single dose at age 9 months, or two doses at 6 and 9 months. Of the children vaccinated at age 9 months, 95% serocoverted, compared with 70% at age 6 months. Delayed-type-hypersensitivity reactions to candida antigen were significantly reduced in both vaccine groups at 6 weeks post-vaccination, but responses to other recall antigens studied were not significantly different from controls. In both vaccine groups, peripheral blood lymphocytes isolated at 6 and 24 weeks after vaccination showed significantly higher expression of activation markers upon in vitro stimulation, and a sustained increase in IL-2 production. These findings suggest prolonged immune activation after measles vaccination at the same time as some reduction in delayed hypersensitivity responses. Further study of the clinical effects of these changes is warranted.

Sero-epidemiology of rubella in the urban population of Addis Ababa, Ethiopia.

We conducted a community-based cluster sample survey of rubella sero-epidemiology in Addis Ababa, Ethiopia in 1994. Among 4666 individuals for whom complete data were available, rubella antibody prevalence was 91% (95% confidence interval: 90, 92). On multivariable analysis, seroprevalence was lower among individuals who were resident in Addis Ababa for 1 year or less. Approx. 50% seroprevalence was attained by age 4 years, and the estimated average age at infection was 5.2 years. The highest age-specific force of infection was estimated to occur in 5- to 9-year-olds. The early age at infection corresponded with a low estimated incidence of congenital rubella syndrome (CRS) of 0.3 per 1000 live births, equivalent to nine cases of CRS in 1994. The predicted critical level of immunity for elimination of rubella via vaccination was 85-91%, requiring 89-96% coverage with a vaccine of 95% effectiveness. Unless very high coverage of rubella vaccine could be guaranteed, the introduction of childhood vaccination could increase the incidence of CRS in Addis Ababa.