I. Adetifa, KEMRI-Wellcome Trust Research Programme, Kenya, Seroepidemiology for monitoring vaccination and informing vaccine policy in Africa

Although vaccines are essential for preventing many severe and often fatal diseases, they are only beneficial when received so their impact is greatly dependent achieving high vaccination coverage. Consequently, vaccination coverage indices are widely used to monitor vaccination programmes. Vaccination coverage is commonly assessed as the proportion of children aged 12-23 months who received the 3rd dose of a diphtheria-pertussis-tetanus (DPT3)-containing vaccine at age 12 months. DPT3 coverage is typically obtained from administrative records (registers in vaccine clinics and records of total doses of vaccines consumed). It can be also obtained from household surveys of vaccine cards/records or by asking caregivers to confirm vaccination by memory recall. Coverage estimates obtained from administrative records frequently overestimate coverage in low and middle-income countries because of errors in tracking consumption of vaccine doses and wrongly estimated target population. While survey methods provide more accurate estimates, they are disruptive to routine health services and expensive. Other weaknesses are incomplete representation of the target population, underreporting, and missing and/or incomplete information. It is important to for estimates of vaccination coverage to be as accurate as possible especially as receiving a vaccine i.e. vaccination does not always result in immunisation which is defined as vaccine-induced protection against the targeted disease. For example, following measles vaccination, the proportions of children who develop protective antibody levels are approximately 85% at 9 months of age and 95% at 12 months of age. Conventional methods for measuring coverage do not tell us what proportion of the population has immunity against the disease of interest.

In high income countries, national serological surveys are conducted to obtain blood samples to measure the proportion of the population that is protected by vaccination. These blood samples are tested for antibodies produced in response to vaccines. As a result, these countries have a longer experience of using these antibody surveys to estimate the burden of diseases before introducing vaccines and assessing the performance of vaccination programmes in reducing disease burden e.g. for hepatitis B. These antibody surveys are also used to identify at-risk groups requiring special vaccination programmes e.g.mass campaigns, and to assess the duration of vaccine induced protection. Serosurveys require reliable vaccination records which are typically available in developed countries. In the developing countries of Africa, I found very limited use of serological surveys to monitor vaccination and to guide revisions of vaccination strategies as seen in high income countries. However, I found that testing for antibodies induced by tetanus vaccine may be useful for this purpose because it overcomes one key limitation of serological surveys i.e. distinguishing between antibodies from natural infection and those resulting from vaccination.

I will investigate the possibility of using antibody testing to monitor vaccination and to compare this to vaccine records in Kilifi, extend this experience to samples from a nationwide survey. This project will benefit from the excellent opportunities provided by the availability of serum samples collected during serological surveys in Kilifi from 2009-2017 and reliable vaccine records from the Kilifi vaccine registry. I will apply statistical methods to antibody test results to identify a reliable mathematic model that reliably predicts vaccination coverage when compared to vaccine records. On identifying this model, I will then carry out a nationwide serological survey, apply the methods validated in Kilifi to the antibody test results to estimate national vaccination coverage, identify at-risk populations with gaps in their immunity and make recommendations for interventions to protect these populations.

Vaccination coverage is currently assessed by via administrative records (health facility registers/vaccine doses consumed) or from household surveys of vaccine cards or recall of childhood vaccination history. These conventional methods over/underestimate coverage because of errors in tracking vaccine doses and wrong assumptions about the size of target population; selection/participation bias, underreporting, and missing or incomplete information. They also provide only very limited insights into population immunity which is important because vaccination does not always result in immunisation.
Serological surveys are regularly used in developed countries to assess the impact of vaccination programmes, to identify at-risk groups via population immunity profiles and have informed revisions to vaccination strategies/schedules (e.g for pertussis and Haemophilus influenzae type b). In our recent review of of the use of serological surveys in the developing countries of Africa, we found very limited use of serosurveys for monitoring vaccination and some evidence in support of measuring tetanus antibodies because unlike other vaccines they they are not confounded by natural infection. None of these studies investigated hepatitis B.
My key objectives are 1) to identify suitable predictive mathematical models of serology for estimating vaccination coverage based primarily on tetanus and hepatitis B antibodies and explore their application to Diphtheria-Pertussis-Tetanus antibodies too; 2) To use validated models from objective 1 to estimate vaccination coverage using national serosurvey data and compare these to administrative and survey-derived coverage estimates. 3) To define age-specific population immunity profiles for vaccine preventable diseases of priority in Kenya.
Collaborating with modellers, I will also explore the application of Markovian cohort models of antibody waning to trivariate antibody data and transmission dynamic models of population immunity.

A) Who will benefit from our research
1) Scientific community, vaccine epidemiologists and mathematical modellers: In addition to sharing results through presentations at scientific meetings, in journals articles, on social media, etc, curated datasets will be made available through the KWTRP dataverse portal according to policy. The dataset will be useful for replication procedures and for extended modelling approaches that may expand the application of mathematical models to robust serology data from a low and middle-income country.
In addition, archived sera from this study can be made available to interested colleagues subject to KWTRP Data Governance Committee approvals for expanded antibody testing and/or development of more multiplexed antibody assays e.g. for hepatitis B.
2) International organisations and institutions working in global health: Our findings will facilitate the incorporation of serological surveys for monitoring vaccination coverage and for guiding vaccine policy in similar settings. These would also be useful for the design of bespoke interventions to improve coverage or targeted to at-risk groups. Seroepidemiology is now the subject of renewed interest by the Gates Foundation and other research funders. The results of this study will be shared with WHO and WHO SAGE for their consideration with a view of making recommendations with global implications where applicable.
3) Wider Research Community in Kenya, UK and Globally
The applicable of mathematical models to serological data will provide a better understanding of vaccination induced immunity and the duration of protection given the examination of antibody decay (waning). Our success here may lead to proposals to KENITAG and KNICC to have serological monitoring incorporated within the core functions of the Kenyan National Vaccines and Immunisation Programme. This may also be adopted regionally and across the continent, in developing countries of south east Asia and other parts of the world.
4) Communities in Kenya: The ultimate goal for studies like this one is to confirm the immunising power of routinely administered vaccines for maximum benefits to the population from both direct and indirect vaccine effects. Improving the understanding of population immunity in relations to vaccination will provide an assessment of the impact of the national immunisation programme, identify communities at-risk and requiring interventions to improve vaccine uptake and coverage. Communities will gain from increased efficiency of the national vaccination programme to reduce morbidity and mortality due to vaccine preventable diseases.