Age-related changes in the rate of disease transmission: implications for the design of vaccination programmes

Mathematical models are developed to aid in the investigation of the implications of heterogeneity in contact with infection within a community, on the design of mass vaccination programmes for the control of childhood viral and bacterial infections in developed countries. Analyses are focused on age-dependency in the rate at which individuals acquire infection, the question of 'who acquires infection from whom', and the implications of genetic variability in susceptibility to infection. Throughout, theoretical predictions are based on parameter estimates obtained from epidemiological studies and are compared with observed temporal trends in disease incidence and age-stratified serological profiles. Analysis of case notification records and serological data suggest that the rate at which individuals acquire many common infections changes from medium to high and then to low levels in the infant, child and teenage plus adult age groups respectively. Such apparent age-dependency in attack rate acts to reduce slightly the predicted levels of herd immunity required for the eradication of infections such as measles, when compared with the predictions of models based on age-independent transmission. The action of maternally derived immunity in prohibiting vaccination in infants, and the broad span of age classes over which vaccination currently takes place in the U.K., however, argue that levels of herd immunity of between 90 and 94% would be required to eliminate measles. Problems surrounding the interpretation of apparent age-related trends in the acquisition of infection and their relevance to the design of vaccination programmes, are discussed in relation to the possible role of genetically based variation in susceptibility to infection and observations on epidemics in 'virgin' populations. Heterogeneous mixing models provide predictions of changes in serology and disease incidence under the impact of mass vaccination which well mirror observed trends in England and Wales.     

Interpretation of serological surveillance data for measles using mathematical models: implications for vaccine strategy.

Serological surveillance of measles immunity has been carried out in England since 1986/7. Results from sera collected in 1989-91 revealed that the proportion of school age children who were susceptible to measles was increasing, following the introduction of the measles, mumps and rubella vaccination programme in October 1988. Mathematical models are used to interpret these data and determine whether this increasing susceptibility is sufficient to allow a resurgence of disease from the low levels achieved by 1993. The models summarize serological profiles by a single parameter, the reproduction number R, which quantifies the level of herd immunity in the population. Results showed that there was cause for concern over the levels of susceptibility to measles, with an epidemic of over 100,000 cases likely in 1995/6. These predictions are consistent with trends in the incidence and age distribution of measles and have enabled the planning of a major vaccination campaign.     

Inadequate immunity to measles in children vaccinated at an early age: effect of revaccination

This report describes a follow-up serological study of 79 Brazilian children who, because of their young age, had failed to develop protective levels of immunity after vaccination against measles. There was serological evidence that infection with wild virus had occurred at a rate of about 17% per annum. Approximately 1½ years after the initial vaccination, 46% of the uninfected children maintained very low levels of neutralizing antibody, but did not have a measurable haemagglutination-inhibition titre. Revaccination did not elicit an IgM response in most children, but stimulated anti-measles IgG production in all of them. In 36% of the children, the IgG titres fell again within three months to levels that may permit reinfection. If it is assumed that some of the persistent titres can be attributed to wild virus infection, the actual effect of revaccination would have been to immunize no more than 60% of the susceptible group. The results suggest that early administration of measles vaccine may produce a cohort of children with inadequate immunity who cannot be fully immunized by revaccination. The implications of these findings for measles immunization programmes are discussed.     

Reconstruction of measles dynamics in a vaccinated population

The evaluation of measles vaccination programmes has been problematic because the change in actual numbers of infections and susceptibles over time cannot be directly observed. In this paper, we present a method for estimating the time series of number of susceptibles and infections, as well as the critical vaccination coverage in a vaccinated population. The proposed method is applied to data on measles outbreaks in The Netherlands. We show that the results are self-consistent and in line with available independent estimates. A potential application of the proposed method lies in detecting the loss of herd immunity and assessing the risk of major outbreaks in vaccinated populations.     

Estimating the number of US children susceptible to measles resulting from COVID-19-related vaccination coverage declines

Measles elimination hinges on vaccination coverage remaining above 95% to retain sufficient community protection. Recent declines in routine measles vaccinations due to the COVID-19 pandemic coupled with prior models indicating the country was close to the 92% herd immunity benchmark are a cause for concern. We evaluated population-level measles susceptibility in the US, including sensitivity analyses accounting for pandemic-related impacts on immunization. We estimated the number of children aged 0–18 currently susceptible to measles and modeled susceptibility proportions in decreased vaccination scenarios. Participants were respondents to the NIS-Teen survey between 2008 and 2017 that also had provider-verified vaccination documentation. The exposure of interest was vaccination with a measles-containing vaccine (MCV), and the age at which they were vaccinated for all doses given. Using age at vaccination, we estimated age-based probabilities of vaccination and modeled population levels of MCV immunization and immunity vs. susceptibility. Currently, 9,145,026 children (13.1%) are estimated to be susceptible to measles. With pandemic level vaccination rates, 15,165,221 children (21.7%) will be susceptible to measles if no attempt at catch-up is made, or 9,454,436 children (13.5%) if catch-up vaccinations mitigate the decline by 2–3%. Models based on increased vaccine hesitancy also show increased susceptibility at national levels, with a 10% increase in hesitancy nationally resulting in 14,925,481 children (21.37%) susceptible to measles, irrespective of pandemic vaccination levels. Current levels of measles immunity remain below herd immunity thresholds. If pandemic-era reductions in childhood immunization are not rectified, population-level immunity to measles is likely to decline further.     

Waning immunity and subclinical measles infections in England

Following the introduction of vaccination against measles, levels of clinical infection have dropped markedly. As we move further into the vaccine era, increasingly many individuals owe their measles immunity to vaccination and have had few (if any) exposures to wild virus. A number of recent reports suggest that vaccinated individuals with low levels of immunity may be at risk of subclinical measles infection. We explore the interplay between levels of infection and immunity over time using a mathematical model that simulates infection, waning and boosting of immunity. We focus particularly on the situation in England, where vaccination has been in place since 1966. Simulations of our model demonstrate a rise in the levels of subclinical measles infection over time, and a corresponding rise in clinical measles infections if vaccination levels are too low. We compare the impact of intervention strategies, and find that the rise in cases is most effectively reduced by 'catch-up' vaccination of children. In recent years, vaccination levels in England have dropped from above 90% in the 1990s to 84% in 2001/2002. We discuss the impact of declining vaccination levels on clinical and subclinical infections.     

Quantitative investigations of different vaccination policies for the control of congenital rubella syndrome (CRS) in the United Kingdom.

The paper examines predictions of the impact of various one-, two- and three-stage vaccination policies on the incidence of congenital rubella syndrome (CRS) in the United Kingdom with the aid of a mathematical model of the transmission dynamics of rubella virus. Parameter estimates for the model are derived from either serological data or case notifications, and special attention is given to the significance of age-related changes in the rate of exposure to rubella infection and heterogeneous mixing between age groups. Where possible, model predictions are compared with observed epidemiological trends. The principal conclusion of the analyses is that benefit is to be gained in the UK, both in the short and long term, by the introduction of a multiple-stage vaccination policy involving high levels of vaccination coverage of young male and female children (at around two years of age) and teenage girls (between the ages of 10-15 years), plus continued surveillance and vaccination of adult women in the child-bearing age classes. Model predictions suggest that to reduce the incidence of CRS in future years, below the level generated by a continuation of the current UK policy (the vaccination of teenage girls), would require high rates of vaccination (greater than 60%) of both boys and girls at around two years of age. Numerical studies also suggest that uniform vaccination coverage levels of greater than 80-85% of young male and female children could, in the long term (40 years or more), eradicate rubella virus from the population. The robustness of these conclusions with respect to the accuracy of parameter estimates and various assumptions concerning the pattern of age-related change in exposure to infections and ''who acquires infection from whom'' is discussed.     

Modelling vaccination programmes against measles in Taiwan

Vaccination has proved a powerful defence against measles. We reappraise measles seroepidemiological data in Taiwan from 1974 to 2004 having robust age-stratified serological information on exposure and immunity to quantitatively characterize measles vaccination programmes. We dynamically model measles seroepidemiology to estimate age-dependent intensity of infection associated with the effects of different contact patterns on pre- and post-vaccination. The WAIFM (who acquires infection from whom) contact matrix is employed to describe the transmission between and within each age group. A deterministic SEIR (susceptible-exposed-infected-recovery) model is used to capture subpopulation dynamics. Our study shows that mass regional or nationwide vaccination programmes could greatly reduce the potential for a major measles epidemic and have strong direct effects on the potential impact of childhood vaccination. We parameterize a predictive model that should reduce the socio-economic costs of measles surveillance in Taiwan and thereby encourage its continuance, especially for preschool children.     

Does education about local vaccination rates and the importance of herd immunity change US parents’ concern about measles?

It is unclear how broadly aware parents are of the concept of herd immunity and whether parents consider community benefits of vaccination when making decisions about their child’s vaccinations. We aimed to determine whether educating parents about community-level benefits of measles, mumps, and rubella (MMR) vaccination and local vaccination rates would impact concern about their child’s risk of measles and risk of a measles outbreak.We conducted an electronic survey among Minnesota parents of children aged 6–18 years in August 2016. We assessed baseline knowledge of herd immunity, asked participants to estimate MMR vaccination coverage in their county, and asked participants to estimate the minimum coverage needed to prevent measles outbreaks. We then delivered a short, educational intervention via the survey to inform participants about the benefits of herd immunity, the actual MMR vaccination coverage in their county, and that at least 95% MMR vaccination coverage is needed to prevent measles outbreaks. Pre- and post-intervention, participants were asked to report how concerned they were that their child might get measles. We used logistic regression models to assess factors associated with awareness of herd immunity, change in concern about one’s child’s measles risk, and overall concern for a measles outbreak.Among 493 participants, 67.8% were aware of herd immunity at baseline. Post-intervention, 40.2% (n = 198) of parents learned that MMR vaccination rates in their county were higher than they expected. All participants found out that their county MMR rates were lower than the measles herd immunity threshold of 95%. Overall, 27.0% (n = 133) of participants reported an increase in concern that their child might get measles after learning about local vaccination coverage and the coverage needed to achieve herd immunity.We found that our short, educational intervention aimed to increase awareness about herd immunity and local vaccination led to an increase in concern about disease risk among less than a third of parents.     

The concept of herd immunity and the design of community-based immunization programmes.

The paper focuses on the concepts of transmission success and herd immunity and their relevance to the design of community-based immunization programmes for the control of infectious diseases. Recent work in a number of areas is reviewed, including the influence of mass vaccination on the average age of infection and the incidence of morbidity due to infection and vaccination, the age window of susceptibility and the problems of vaccine programme design in developing countries, the interaction between vaccine efficacy and vaccine safety and the design of vaccination programmes for the control of sexually transmitted infections. Discussions centre on the interplay between an understanding of the transmission dynamics of an infection and the design of community-based control programmes.     

A population profile of measles susceptibility in Tianjin,China

BackgroundMeasles is a highly infectious illness requiring herd immunity of 95% to interrupt transmission. Measles is targeted for elimination in China, which has not reached elimination goals despite high vaccination coverage. We developed a population profile of measles immunity among residents aged 0–49 years in Tianjin, China.MethodsParticipants were either from community population registers or community immunization records. Measles IgG antibody status was assessed using dried blood spots. We examined the association between measles IgG antibody status and independent variables including urbanicity, sex, vaccination, measles history, and age.Results2818 people were enrolled. The proportion measles IgG negative increased from 50.7% for infants aged 1 month to 98.3% for those aged 7 months. After 8 months, the age of vaccination eligibility, the proportion of infants and children measles IgG negative decreased. Overall, 7.8% of participants 9 months of age or older lacked measles immunity including over 10% of those 20–39 years. Age and vaccination status were significantly associated with measles IgG status in the multivariable model. The odds of positive IgG status were 0.337 times as high for unvaccinated compared to vaccinated (95% CI: 0.217, 0.524).ConclusionsThe proportion of persons in Tianjin, China immune to measles was lower than herd immunity threshold with less than 90% of people aged 20–39 years demonstrating protection. Immunization programs in Tianjin have been successful in vaccinating younger age groups although high immunization coverage in infants and children alone would not provide protective herd immunity, given the large proportion of non-immune adults.     

Dynamics and control of measles in Portugal: accessing the impact of anticipating the age for the first dose of MMR from 15 to 12 months of age

The all-time low incidence of measles in Portugal in the recent years, raises questions regarding whether the disease has been eliminated, the role of recent control measures, and the epidemiological consequences of the rise in the proportion of newborns to vaccinated mothers, as opposed to those born to mothers who acquired immunity by natural infection. We estimate the vaccination coverage against measles in Portugal on a cohort-by-cohort basis, and incorporate this information into an age-structured seasonally-driven mathematical model aimed at reproducing measles dynamics in the past decades. The model reproduces documented trends in disease notifications and the serological profile of the Portuguese population, as estimated by a recent National Serological Survey. We provide evidence that the effective reproduction number (R(e)) of measles has been driven below 1 in Portugal, and that sustained measles elimination is crucially dependent upon the maintenance of a high (>95%) coverage with the MMR I vaccine in the future. If the vaccination coverage decreases to levels around 90% the anticipation of the first dose of the MMR I from 15 to 12 months of age, will ensure that R(e) remains below 1.     

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.     

An increasing,potentially measles-susceptible population over time after vaccination in Korea

BackgroundIn Korea, measles occurs mainly in infants <12 months of age, who are unvaccinated. In addition, vaccine populations, including adolescents and young adults, can become infected though importation. Thus, the question arises whether the current level of herd immunity in Korea is now insufficient for protecting against measles infection.MethodsAge-specific measles seroprevalence was evaluated by performing enzyme immunoassays and plaque reduction-neutralization tests on 3050 subjects aged 0–50 years (birth cohort 1964–2014) and 480 subjects aged 2–30 years (birth cohort 1984–2012).ResultsThe overall seropositivity and measles antibody concentrations were 71.5% and 1366 mIU/mL, respectively. Progressive decline in antibody levels and seropositivity were observed over time after vaccination in infants, adolescents, and young adults. The accumulation of potentially susceptible individuals in the population was confirmed by comparing data from 2010 and 2014 seroprevalence surveys. The statistical correlation between measles incidence and measles seronegativity was determined.ConclusionsWaning levels of measles antibodies with increasing time post-vaccination suggests that measles susceptibility is potentially increasing in Korea. This trend may be related to limitations of vaccine-induced immunity in the absence of natural boosting by the wild virus, compared to naturally acquired immunity triggered by measles infection. This study provides an important view into the current measles herd immunity in Korea.     

Measles in England and Wales--III: Assessing published predictions of the impact of vaccination on incidence

Published predictions of the impact which different levels of vaccination should have on measles incidence are discussed in the context of observed data on vaccine uptake and measles incidence in England and Wales. Discrepancies are noted between prediction and observation with regard to the effect of vaccination on epidemic periodicity, epidemic size, age distribution of cases, and the disappearance of measles from communities. These errors are attributable to failures to recognize the implications of seasonal trends in incidence, age dependence of risk, and the non-homogeneity of human populations. Predictive models are useful hypotheses, but should be assessed critically against observation.     

The concept of herd immunity applied to the evaluation of vaccination programs

The article concerns the definition and ways of estimation of indicators of herd immunity as applied to the analysis of the efficiency of vaccination programmes. Some important factors are discussed which determine the proportion of vaccinated individuals in the population necessary for decrease of incidence and eventually for elimination of the disease from a population. The problems related to definition and calculation of herd immunity in populations non uniform in terms of individual risk of infection are discussed.     

Estimating contact-adjusted immunity levels against measles in South Korea and prospects for maintaining elimination status

Measles has been reemerging in South Korea since December 2018 resulting in 185 cases by September 2019.We calculated contact-adjusted immunity levels against measles in South Korea using national seroprevalence data in 2014, vaccination uptake rates, and an age-specific contact matrix. We further explored options to achieve a contact-adjusted immunity level of 93% for herd immunity.The assessed contact-adjusted immunity level has increased from 86% in 2014 to 92% in 2018. Herd immunity could be achieved with immunizing 50% of susceptibles among birth cohorts 1999–2003 in 2018.Contact-adjusted immunity levels against measles have increased recently in South Korea, although they might not yet be high enough to guarantee herd immunity.     

Measles immunity over two decades in two large Italian Regions: How far is the elimination goal?

In Italy, the inclusion of measles vaccine in children immunization schedule and the promotion of national mass vaccination campaigns increased measles vaccination coverage. However, measles outbreaks continue to occur increasingly involving adolescents and adults. The aim of this study was to evaluate the prevalence to measles antibody in a sample of Italian population between 1993 and 2018.Human serum samples from subjects aged 3–40 years were collected between 1993 and 2018 and tested for measles IgG antibodies by commercial ELISA.During the study period, the 3–10-year-old age group showed the most important change, with a significant increase in 2003–2007 in both seroprevalence and IgG levels, followed by a slow decrease. The 11–18-year-old age group showed relatively stable seroprevalence rates and IgG levels over the years. The 19–30-year-old group showed stable seroprevalence rates, albeit with a decrease in IgG levels. After a significant increase in 1999–2002, the 31–40-year-old age group had high seroprevalence rates and IgG levels.Despite efforts at national level for implementing measles vaccination, a large proportion of the population is still susceptible to measles. Even if vaccination coverage increases enough to achieve the level of immunization required for herd immunity in new birth cohorts, outbreaks will continue to occur if there are immunity gaps in older age groups. Establishing policies for measles vaccination targeting adult population is needed to close immunity gaps and reach the elimination goal.     

Immunity against infectious diseases: predictive value of self-reported history of vaccination and disease.

OBJECTIVE: To determine whether self-reported history of disease and/or vaccination is predictive of immunity against hepatitis B, varicella, rubella, mumps, and measles. DESIGN: The seroprevalence of viral antibodies and the predictive value of a self-report questionnaire were determined for 616 paramedical students who matriculated into Padua Medical School (Padua, Italy) during 2003-2005. RESULTS: The majority of subjects (86.9%) remembered being vaccinated against hepatitis B but had no recollection of disease. Among vaccinees, 1.5% showed markers of previous infection, 6.7% tested negative for anti-hepatitis B virus surface antigen (anti-HBsAg) antibodies, and 91.8% tested positive for anti-HBsAg. Self-reported vaccination history had a positive predictive value of 93.2% for test results positive for immunity against hepatitis B. Immunity against varicella (93.7% of subjects) and rubella (95.5%) was high, compared with immunity against mumps (79.9%) and measles (83.1%). In addition, results of tests for detection of immunity against mumps and measles were equivocal for more than 7% of subjects, probably because their vaccination regimen was not completed. Self-reported histories of varicella disease and rubella disease and vaccination had high positive predictive values (greater than 98% each) for testing positive for antiviral antibodies, compared with self-reported histories of mumps disease and vaccination and measles disease and vaccination; however, high positive predictive values were observed for self-reported histories of mumps only (92.0%) and measles only (94.7%). CONCLUSIONS: The self-report questionnaire used in this study did not accurately predict immunity against 5 transmittable but vaccine-preventable diseases. A complete serological evaluation of healthcare workers, followed by vaccination of those with negative or equivocal results of serological tests, is an appropriate measure to decrease the risk of infection in this population.     

Ten years of serological surveillance in England and Wales: methods, results, implications and action

BACKGROUND: The first age-stratified serological survey of antibody to measles, mumps and rubella in the UK was conducted in 1986/87 prior to the introduction of MMR vaccine into the immunization programme. Serum collection and testing have continued annually, allowing trends over time to be monitored. These sera have also been available for ad hoc surveys of other infections. METHODS: Residual sera are collected in participating laboratories and sent to a central store where they are irrevocably unlinked from identifying data. A unique identity number is assigned to each serum and details of age and sex are collated on a database. The sera are accessed for testing as required. RESULTS: The results of recurring and other surveys performed over the last ten years are presented. These demonstrate that opportunistic serum samples are an ideal resource for serological surveillance programmes. CONCLUSIONS: The serological surveillance programme has provided past exposure profiles for many infections. These data have resulted in a number of national policy changes and have been instrumental in shaping the UK vaccination programme.