Two-dose measles–rubella vaccine schedule for measles–rubella elimination

Measles and rubella are directly transmitted via the respiratory route. Both are vaccine-preventable diseases. Since there is no extra-human virus reservoir, these can be eliminated from a country and eradicated globally, if a predicted level of herd immunity can be reached through vaccination, prior to the age of risk of infection by the target agent1. The proportion of immune individuals in the community is represented by the term herd immunity2. The herd immunity for disease elimination must be acquired through vaccination and not though infection because it will result in agent amplification that perpetuates endemic transmission.

The necessary vaccination coverage value can be derived through simple formulae using two epidemiological parameters of disease that are interrelated, namely, contagiousness and age distribution1. The higher the contagiousness, the lower the age when disease strikes, and higher the required herd immunity to block transmission. The yardstick of contagiousness is the ‘force of infection’ which is quantified as ‘basic reproduction number’ R₀, which in turn is derived from the age distribution of disease – represented by its ‘median age’1,2. The formula to derive R₀ is 1+life expectancy/median age and that to derive immunization coverage is 1 minus 1/R₀1.

The median age of measles in India in the pre-vaccination times was ~30 months, R₀ ~25 and ‘immunization’ coverage needed for interrupting transmission ~96 per cent1,3-5. Obviously, the vaccine should typically have high efficacy ( near - 100 %), to equate herd immunity with vaccination coverage. Vaccination should be done at a faster pace than virus transmission. Measles occurred from ~six months of age and saturated the population before 10 yr4-6. For sake of clarity, in this context, we may use the term immunization when vaccination is given before infection. Achieving ~96 per cent immunization coverage before 24 months of age would provide the required ~96 per cent herd immunity for interrupting virus transmission, provided that near-100 per cent vaccine efficacy is guaranteed.

The median age of rubella is during adolescence7, for R₀ ~5 to 7 and immunization coverage required for interruption of transmission is ~80-86 per cent. The seroconversion rate after one dose of rubella vaccine at nine months is >95 per cent8. Therefore, when measles-rubella (MR) vaccination coverage with one dose reaches >90 per cent during infancy, rubella transmission will cease. As rubella is far less contagious, the transmission does not saturate even by childbearing age. Rubella per se in children or adults is inconsequential except during pregnancy, when the risk of congenital rubella is high9.

Measles virus transmission saturates children; hence, all mothers are immune, and all infants are born with maternal antibody, which is highly protective against measles, as long as its level remains adequate. The age of maternal antibody protection raged from ~6 - 12 months, depending on the antibody levels in mothers4-6.

Measles virus in the vaccine must infect to elicit immune response. Maternal antibody against measles interferes with vaccine virus infection, impairing the immunogenic efficacy of measles vaccine. Hence, fixing an age for ‘routine vaccination’ to induce immunity was tightrope walk – balancing two opposing values: age of risk of disease, which begins from six months, and age of minimum risk of maternal antibody interference, which is ~12 months. The best compromise was shown with evidence, as nine months6,10, which became the norm when the Expanded Programme on Immunization (EPI) was established by the World Health Organization (WHO), in 197411.

Maternal antibody interference is typically graded by the antibody level at the point of time when the vaccine is given. India introduced the measles vaccine in EPI in 1985, in sixty districts, adding sixty more each year, until all districts were covered in 1990, when the name of National Immunization Programme changed from EPI to Universal Immunization Programme (UIP)12. Now 37 years after the introduction of measles vaccination, the vaccine induced antibody levels in many mothers, would expectedly be lower as compared to when it was induced exclusively by natural infection.

As part of a global agenda for eradication of measles and rubella, India has set a time target for MR elimination as of December 2023, (after two postponements – 2015 and 2020)13,14. The India Expert Advisory Group on Measles & Rubella (IEAG-MR) has drawn a ‘road map’ for MR elimination on target time13-15. The strategy is to reach at least 95 per cent coverage with the second dose of MR vaccine during the second year of life, in every district and sub-district blocks13,15. For this, the first-dose coverage should expectedly surpass 95 per cent.

The seroconversion rate to a dose of measles vaccine at 6-8 months is only ~87 per cent, improving to ~94 per cent at 9-11 months and 98 per cent at 12-15 months16. The geometric mean titre of virus-neutralizing antibody was low when vaccinated at 6-8 months, increasing to ~50 at 9-11 months and >65 at 12-15 months16. Hence, one dose at 9-11 months, as originally stipulated by UIP, leaves a wide gap in immunity. Therefore, measles remained endemic even in well-vaccinated districts, with most cases in one-dose recipients and with an upward age shift17. Even 100 per cent coverage with one dose would fail to reach the required 95-96 per cent herd immunity for measles elimination. A second dose in the second year of life is needed to bridge the gap, as is the current UIP policy.

The two-dose schedule has a potential problem – in some children, the response to the second dose was reported to be absent or low, instead of covering the immunity gap18. In a study in India, conducted some 15 yr ago, this problem was alarmingly serious – amongst those given the first dose of measles vaccine at nine months, only 21.4 per cent had detectable measles antibody at 4-6 yr of age, which rose only to 72.6 per cent post-second dose19. There is a scientific explanation for this unanticipated problem20,21.

The unanswered question facing IEAG was if the recommended two-dose schedule will result in near-100 per cent seroconversion, or, if the first dose given during 9-11 months would impair the second-dose response, jeopardizing success of MR elimination.

Sri Lanka, Maldives, Bhutan, Timor-Leste and North Korea have eliminated measles and rubella using the same second-dose schedule22. However, IEAG desired a more recent study specific for India, to re-visit the question. It is now well answered by the study be Verma et al23 published in this issue of the IJMR.

The antibody response frequency was found to be 88.7 per cent after one dose given between 9-12 months and 100 per cent after the second dose which was given during 15-24 months20. No impairment of immune response to the second dose was observed. India is hoping for MR elimination by end 2023, by achieving at least 95 per cent coverage with the MR vaccine’s second dose in the second year of life13-15. The two-dose immunization schedule will be adequate for MR elimination.

The success of MR elimination by the end 2023 depends on achieving the required immunization coverage in every district.