Abstract and Introduction
Abstract
Measles and rubella are major vaccine-preventable causes of child mortality and disability. They have been eliminated from the Americas and some other regions have also come close to elimination. In this paper, we review regional progress toward measles and rubella control/elimination goals, describe the recent epidemiology of these infections and discuss challenges to achieving the goals. Globally, measles vaccination is estimated to prevent nearly 2 million deaths each year. Despite this remarkable progress, large measles outbreaks have occurred in recent years, often involving older persons who were not vaccinated in earlier years. Such an occurrence would be particularly damaging for rubella control programmes as it could lead to peaks in congenital rubella syndrome. Challenges to achieving and sustaining high vaccination coverage include civil conflict, weak health systems, geographic, cultural and economic barriers to reaching certain population groups and inadequate monitoring and use of data for action. Countries and regions aiming to eliminate measles and control rubella urgently need to improve the implementation and monitoring of both routine and mass vaccination campaign strategies.
Introduction
Before measles vaccine was introduced, measles was one of the most severe childhood illnesses leading to at least 2 million deaths per year,[1,2] and it was a major cause of blindness in low income countries.[3] The acute illness is characterized by fever and rash with coryza, cough or conjunctivitis. Measles virus is a potent immune modulator and common complications that often require hospital care include pneumonia, diarrhea and dysentery. Clinical, virological and pathological features are reviewed elsewhere.[4] Since licensure of live attenuated measles vaccine 50 years ago, estimated global measles mortality has fallen to <7% of its pre-vaccination levels.[5] Elimination of measles is biologically feasible,[6] and programmatic feasibility has been demonstrated in the Americas, where the last indigenous case occurred in November 2002.[7]
Rubella infection is another cause of fever and rash in children which is usually mild when acquired postnatally[8] but may result in fetal loss or severe disability after primary infection in the first trimester of pregnancy.[8–10] Estimates of the global burden of congenital rubella syndrome (CRS) derive from models of the risk of infection in pregnancy, using serological data on the age-specific prevalence of rubella antibodies. Based on literature reviewed in 1996, approximately 110,000 cases of CRS (uncertainty bounds ranging from ~14,000–308,000) were estimated to occur each year in developing countries which did not vaccinate against rubella,[11] with highest numbers predicted in Africa and south east Asia. A review of data up to 2010 resulted in estimates of a similar order of magnitude.[12]
Measles and rubella vaccines are live, attenuated viral vaccines[4,13] which are most effective when administered after maternal antibody is lost (this passively acquired antibody declines exponentially from about age 2–3 months onward and is undetectable in most infants by 9–12 months of age). They are available as separate or combined vaccines and administered by subcutaneous or intramuscular injection, although alternative routes of vaccination such as aerosol or intranasal have shown promise.[13–18] Sabin and colleagues pioneered the use of aerosol measles vaccines in Mexico in the 1980s.[19] Subsequently, trials in South Africa and Mexico showed that sero-responses and persistence of boosted antibody levels were better following measles vaccination of school children by aerosol than subcutaneous vaccination[20–22] and some studies in infants have also shown good responses.[14,17,18,23] Aerosol administration of dry-powder measles vaccine is also being evaluated.[24] Cost–effectiveness analyses[24] and stakeholder opinion[25] suggest that the aerosol route could be efficient and help programs to achieve measles control goals. A recent pivotal Phase II/III trial conducted in India under the auspices of the WHO measles aerosol project, however, showed that following vaccination at age 9 months, the per-protocol seropositivity in the aerosol arm was 85.4% (95% CI: 82.5–87.9%) as compared to 94.6% (95% CI: 92.7–96.1%) in the subcutaneous arm, with the difference in seropositivity and the upper limit of the confidence interval both being greater than the non-inferiority margin of 5% defined in the study protocol. SAGE members concluded that the tested aerosol vaccine may not be suitable for primary vaccination of infants against measles but recommended that further research on measles-rubella (MR) aerosol be conducted.[26]
Combination MR vaccines used in industrialized countries usually also include mumps vaccine, but the burden of mumps infection is poorly described in low income countries. Based on mortality and disease burden, WHO considers measles control and the prevention of CRS to be higher priorities than the control of mumps.[27] We therefore do not discuss mumps in this article.
A single dose of measles-containing vaccine (MCV1) induces antibody responses among 85–90% of infants at age 9 months and over 95% of infants vaccinated at age 11 months or above (reviewed in[28]). Field studies show median vaccine effectiveness (VE) of 84.0% (interquartile range [IQR]: 72.0–95.0%) and 92.5% (IQR: 84.8–97.0%) after vaccination at 9–11 and >12 months, respectively.[29] Infants may respond to vaccine at an earlier age, once most mothers have vaccine-induced rather than natural immunity, since the former results in lower antibody levels being transferred in utero.[30] In low transmission settings, it is feasible to vaccinate at the age of 15 months when effectiveness is higher.[31,32] By contrast, the WHO recommends vaccination at age 9 months in countries with ongoing transmission in which the risk of measles mortality among infants remains high.[28,33,34] To eliminate measles, a second dose of vaccine is recommended;[33] field studies show median VE for two doses of 94.1% (IQR: 88.3–98.3%) compared with no vaccination.[29] Responses to measles vaccine are lower in HIV-infected children,[35–37] but their high mortality has reduced any resulting effect on population immunity.[38,39] The potential role of revaccination of HIV-infected children on antiretroviral therapy in low-income countries is under evaluation.[40] Rubella-containing vaccines (RCV) currently distributed in most countries contain the RA 27/3 strain prepared in human diploid cell culture.[13] Seroconversion rates of 94–98% have been reported after vaccination at the age of 9 months or older (reviewed in [41] and [42]).
Immunity is long-lasting among persons who develop a primary immune response to measles and rubella vaccines. Antibody levels wane after vaccination,[43] but are boosted rapidly on exposure to infection which may be subclinical or associated with mild illness. For rubella, such re-infection of pregnant women has very low risk of transmission to the fetus.[44,45] Antibody levels are boosted after revaccination of persons whose antibody levels have waned but fall again quickly.[28]
Rubella vaccination is cost effective in industrialized and middle-income countries.[46] In 2010, however, over two-thirds of the global birth cohort lived in countries that did not include rubella vaccination in their national immunization programme, due to a lack of empirical data on disease burden (only a minority of cases are seen at medical facilities having the capacity to diagnose CRS[47,48]), the increased cost of combined MR vaccine compared to single-antigen measles vaccine, and concerns about potential increases in CRS if adequate coverage of rubella vaccination could not be assured and sustained.[49]
As interest in measles elimination increases,[50] there are calls to include rubella in measles control and elimination activities.[51–53] The GAVI alliance, a public-private partnership of charitable organizations, national governments and international organizations such as WHO and UNICEF, has supported the introduction of new vaccines in low-income countries for more than a decade and has also contributed funding for measles campaigns. There are currently 56 GAVI-eligible countries, although not all are available for all types of support.[201] Recently, GAVI has made funding available for MR catch-up campaigns in countries that can achieve 80% immunization coverage (via routine, or routine and campaigns); and can finance the introduction of rubella vaccine into their routine program immediately following the catch-up campaign.[54] GAVI will also fund second dose measles vaccine (MCV2) costs in eligible countries, though not the rubella component. In 2012, WHO and partners published the first global combined strategic plan for measles and rubella control and elimination.[202] In this paper, we briefly review some principles of measles and rubella vaccination and describe progress toward measles control and elimination and current challenges in different WHO regions. We then discuss the implications of the experience with measles vaccination programmes for rubella control and elimination.
Expert Rev Vaccines. 2013;12(8):917-932. © 2013 Expert Reviews Ltd.
