The implementation of measles vaccination policies worldwide has decreased the mortality rate attributed to measles by 78% between 2000 and 2008.1 Routine measles vaccination coverage in Europe and Central Asia has increased to 93%, thus resulting steadily in <1000 deaths per year from 1999 to 2004. During the same period, the most significant reduction in mortality has been observed in the sub-Saharan African region (from 530,000 to 216,000 deaths per year) due to the increase in measles vaccination coverage (from 49% to 65%).2 However, outbreaks continue to occur highlighting the major obstacles to measles eradication, phenomena that are directly associated with pockets of susceptible children and adults due to accumulation of subjects with suboptimal vaccination coverage. Moreover, globalization, including enhanced travel and migration of population groups, impedes the elimination of measles.3,4 Recent data support that infants too young to get immunized are at increased risk due to earlier loss of maternal antibodies in offspring of vaccinated mothers.5 Moreover, current outbreaks have shown that although the majority of cases involve susceptible young adults, there has been an increase in the percentage of infants affected.6,7 In Germany, the age-specific incidence of measles has increased between 2001 and 2006, while in France an increase in the percentage of infants affected was observed between 2008 and 2010.8,9 Table 1 summarizes the most recent measles outbreaks over the past couple of years in the developed world and the percentage of infants involved. This article reviews the window of susceptibility for infection during infancy, occurring from the loss of passively acquired maternal antibodies through the first dose of recommended vaccination, and also identifies potential solutions in light of current global epidemics.
The combined live attenuated measles-mumps-rubella vaccine (MMR) was introduced in the United States in 1982 to be administered at ≥12 months of age.1 In Europe, MMR was introduced in 1988 and has been included ever since in World Health Organization’s Expanded Program on Immunization.16 Currently, in European countries the first dose of MMR is administered between 11 and 18 months of age.17 In certain countries, including France, an early start is recommended for children attending day care (first dose at 9 months, followed by second dose at 12–15 months).18 In addition, in United States one dose of MMR (or monovalent against measles, if not available) is recommended prior to traveling abroad for all infants from 6 to 11 months of age.19 In developing countries, the vaccine has been administered as early as 4.5 months of age for research purposes, emphasizing on the importance of similar vaccination practices during epidemics.20,21
PASSIVE TRANSPLACENTAL IMMUNITY
During the first months of life, infants are protected against measles by transplacentally derived maternal antibodies. Until recently, most women of child-bearing age were immune to measles either by natural infection or through active vaccination with repeated natural boosting through contact with the circulating wild-type virus.22 The interval between the nadir of transplacental maternal antibodies and the initiation of measles vaccination should be as brief as possible, particularly in view of the potential risk of early exposure to the virus.5,23 Several studies in the recent literature suggest that infants are susceptible to measles well before the initiation of the immunization schedule.20,22,24–27
In a prospective cohort study of 207 infants by Leuridan et al,24 >99% of infants of vaccinated women and 95% of infants of naturally immune women had lost maternal antibodies by the age of 6 months. In a prospective study, Klinge et al22 showed that only 5% of 118 German infants older than 9 months of age had detectable antibodies against measles. Leineweber et al evaluated prospectively a cohort of 71 full-term and 101 preterm infants. Between 6 and 12 months of age, <20% of infants born after 32 weeks of gestation had detectable measles antibodies; all infants born prior to 32 weeks of gestation had undetectable measles antibodies.25 In a study of 138 infants, Jo et al26 reported that the seropositivity rates and measles-specific IgG levels decreased rapidly after 3 months of age.
This situation is similar, if not worse, in developing countries where infants lose maternally acquired antibodies more rapidly than those in developed countries. Shilpi et al27 reported that only 25.5% of the 147 Bangladeshi infants studied had protective measles antibody levels between 2 and 5 months of age, and none had protective levels from 5 months onward. In a study conducted in Nigeria, Hartter et al showed that only 17% of the 4-month-old infants were protected against measles. The overall prevalence of measles antibodies of 206 infants up to 9 months of age was 45%. Moreover, the prevalence of measles antibodies was limited to 32% among infants aged 3 months and 2% among those aged 6–9 months.20
In conclusion, data from both developed and developing countries indicate that the majority of children are susceptible to measles by the age of 6 months, increasing the window of susceptibility in infants too young to get immunized. This is mainly due to the increased proportion of mothers being immunized against measles rather than naturally infected.
SUSCEPTIBLE INFANTS AND EARLIER VACCINATION
Earlier immunization against measles may potentially minimize the window of susceptibility between waning of transplacentally acquired measles antibodies and the initiation of measles vaccination for infants. However, there exist potential barriers to the adoption of earlier immunization schedules, including the inherent immaturity of the immune system of young infants, as well as the potential interference by maternal antibodies on vaccine responses.
Several studies evaluating these obstacles are mentioned in the recent literature. A prospective study assessed a cohort of 248 infants aged 6 and 9 months who were immunized with live measles virus vaccine. All infants consequently received the MMR-II dose at the age of 12 months. When the 9-month-old infants were immunized in the absence of passive maternal antibodies, their immune response was equivalent to that of the 12-month-old children, thus indicating that the former have no intrinsic impairment of B-cell function. However, the capacity of the infant immune system to generate humoral response to measles vaccine was markedly diminished among infants aged 6 months.28
On the other hand, in a study in São Paulo with the majority (94%) of children being seronegative at 6 months of age, regardless of the cause of maternal immunity, the response to measles vaccination did not exceed 54% at 8 months of age and depleted throughout 9 months.29 Moreover, Carson et al30 evaluated prospectively the response of 300 infants to early measles vaccination and confirmed that vaccine strain AIK-C could successfully prime young infants. In addition, in another study in the area of Bandim Health Project (Guinea-Bissau), among a cohort of 1333 children, 441 were vaccinated at the age of 4.5 months using the Edmonston-Zagreb vaccine while controls (892 infants) were vaccinated at the age of 9 months.21 It is noteworthy that while prior to vaccination, 28% and 5% of children 4.5 and 9 months old, respectively, had protective titers of maternal antibodies, 77% of the infants in the early vaccination group had protective measles titers at the age of 9 months. More importantly, it was shown that the efficacy of early vaccination for children with serologically confirmed measles and definite clinical measles was 94%. Hence, measles outbreaks may be curtailed by vaccination using the Edmonston-Zagreb vaccine as early as 4.5 months of age.21
The main determinant of maternal antibody–mediated inhibition of immune responses is represented by the titer of maternal antibodies present at the time of immunization, or rather by the ratio of maternal antibodies to vaccine antigen administered. It is thus obvious that late immunization is more efficient than early immunization, even in the presence of maternal antibodies. However, such a strategy would fail to prevent early cases of infection, which are concomitantly most often of greater severity.
DNA vaccines that express viral proteins could potentially serve as a solution providing adequate protection from severe illness among newborns and young infants during the period of susceptibility. This would still allow for a boost immunization with the live attenuated measles virus vaccine, as recommended, after 9 months of age. A recent study evaluating neonatal mice born to naive and measles-immune mothers demonstrated that Sindbis virus replicon–based DNA vaccines elicited antibody levels above the protective threshold and cellular immune responses, despite the presence of passively acquired antibodies.31 However, neither DNA nor vectored vaccines are expected to be available for clinical trials during the near future.32
MEASLES IN INFANTS TOO YOUNG TO GET IMMUNIZED; CALL FOR ACTION
Vaccination against measles in one generation increases the possibility of infection in the next. Over the past 2 decades, the proportion of vaccinees in the population has increased, with the latter gradually replacing individuals with lifelong protection acquired from natural infection.33 Infants become more susceptible as passively acquired maternal antibodies become less and are catabolized earlier.5,34 This is directly linked to the fact that vaccine-induced immunity is less robust and less durable than immunity conferred by natural infection. More importantly however, the waning of antibodies is accelerated in the absence of re-exposure to wild-type virus and, therefore, lack of natural boosting immunity.31 It is also important to refer to the continuously increasing age of parity in the western population, with an increased interval between childhood vaccination and childbirth. As a result of all the aforementioned factors, a decrease in transmitted maternal protection is observed.5 Even if the first dose of MMR was administered at 6 months of age, many younger infants who have no maternal antibodies would remain susceptible to the disease.24 Therefore, until novel vaccines that provide adequate protection to young infants are designed, prevention through herd immunity is mostly important. Yet, as recent epidemics have shown, insufficient vaccine coverage among children and young adults has resulted in the accumulation of susceptible subjects over the past 2 decades.6,9–14
In conclusion, current measles outbreaks have mainly affected adolescents and young adults due to the increased number of undervaccinated birth cohorts. At the same time, due to the decreased maternal protection provided by vaccinated mothers, infants too young to get immunized are at increased risk. To prevent outbreaks, interrupt measles circulation and protect infants too young to get immunized, strong efforts should be made to achieve and maintain routine coverage over 95%,35 and to immunize susceptible children, adolescents and adults through catch-up vaccination.
2. Centers for Disease Control and Prevention.. Progress in reducing global measles deaths, 1999–2004 MMWR.. 2006;55:247–249
3. Dannetun E, Tegnell A, Hermansson G, et al. Timeliness of MMR vaccination–influence on vaccination coverage. Vaccine. 2004;22:4228–4232
4. De Serres G, Gay NJ, Farrington CP. Epidemiology of transmissible diseases after elimination. Am J Epidemiol. 2000;151:1039–48; discussion 1049
5. Leuridan E, Van Damme P. Passive transmission and persistence of naturally acquired or vaccine-induced maternal antibodies against measles in newborns. Vaccine. 2007;25:6296–6304
6. Bozzola E, Quondamcarlo A, Krzysztofiak A, et al. Re-emergence of measles in young infants. Pediatr Infect Dis J. 2011;30:271
7. Grgic-Vitek M, Frelih T, Ucakar V, et al. Spotlight on measles 2010: a cluster of measles in a hospital setting in Slovenia, March 2010. Euro Surveill. 2010;15:pii: 19573
8. Wichmann O, Hellenbrand W, Sagebiel D, et al. Large measles outbreak at a German public school, 2006. Pediatr Infect Dis J. 2007;26:782–786
9. Parent du Châtelet I, Antona D, Freymuth F, et al. Spotlight on measles 2010: update on the ongoing measles outbreak in France 2008–2010 Euro Surveill. 2010;15:pii: 19656
10. Stanescu A, Janta D, Lupulescu E, et al. Ongoing measles outbreak in Romania, 2011. Euro Surveill. 2011;16:pii:19932.
11. Marinova L, Muscat M, Mihneva Z, et al. An update on an ongoing measles outbreak in Bulgaria, April-November 2009. Euro Surveill. 2009;14:pii: 19442
12. Gee S, Cotter S, O’Flanagan DNational Incident Management Team. . Spotlight on measles 2010: measles outbreak in Ireland 2009-2010. Euro Surveill. 2010;15:pii: 19500.
13. Pervanidou D, Horefti E, Patrinos S, et al. Spotlight on measles 2010: ongoing measles outbreak in Greece, January-July 2010. Euro Surveill. 2010;15:pii: 19629.
14. Centers for Disease Control and Prevention.. Measles—United States, January–May 20, 2011. MMWR. 2011;60:666–668
15. Pabst HF, Spady DW, Marusyk RG, et al. Reduced measles immunity in infants in a well-vaccinated population. Pediatr Infect Dis J. 1992;11:525–529
16. Jefferson T, Price D, Demicheli V, et al.European Research Program for Improved Vaccine Safety Surveillance (EUSAFEVAC) Project. Unintended events following immunization with MMR: a systematic review. Vaccine. 2003;21:3954–3960
18. Gagneur A, Pinquier D. Letter to the editor. Spotlight on measles 2010: timely administration of the first dose of measles vaccine in the context of an ongoing measles outbreak in France. Euro Surveill. 2010;15:19689; author reply 19686
20. Hartter HK, Oyedele OI, Dietz K, et al. Placental transfer and decay of maternally acquired antimeasles antibodies in Nigerian children. Pediatr Infect Dis J. 2000;19:635–641
21. Martins CL, Garly ML, Balé C, et al. Protective efficacy of standard Edmonston-Zagreb measles vaccination in infants aged 4.5 months: interim analysis of a randomised clinical trial. BMJ. 2008;337:a661
22. Klinge J, Lugauer S, Korn K, et al. Comparison of immunogenicity and reactogenicity of a measles, mumps and rubella (MMR) vaccine in German children vaccinated at 9-11, 12-14 or 15-17 months of age. Vaccine. 2000;18:3134–3140
23. Glezen WP. Effect of maternal antibodies on the infant immune response. Vaccine. 2003;21:3389–3392
24. Leuridan E, Hens N, Hutse V, et al. Early waning of maternal measles antibodies in era of measles elimination: longitudinal study. BMJ. 2010;340:c1626
25. Leineweber B, Grote V, Schaad UB, et al. Transplacentally acquired immunoglobulin G antibodies against measles, mumps, rubella and varicella-zoster virus in preterm and full term newborns. Pediatr Infect Dis J. 2004;23:361–363
26. Jo DS, Lee SH, Kim SY. Measles IgG titer of mothers and infants under 12 months of age in Korea. 26th Annual Meeting of the European Society of Pediatric Infectious Diseases, Graz, Austria. May 13–17, 2008 [Abstract 636]
27. Shilpi T, Sattar H, Miah MR. Determining infants’ age for measles vaccination based on persistence of protective level of maternal measles antibody. Bangladesh Med Res Counc Bull. 2009;35:101–104
28. Gans H, Yasukawa L, Rinki M, et al. Immune responses to measles and mumps vaccination of infants at 6, 9, and 12 months. J Infect Dis. 2001;184:817–826
29. Zanetta RA, Amaku M, Azevedo RS, et al. Optimal age for vaccination against measles in the State of São Paulo, Brazil, taking into account the mother’s serostatus. Vaccine. 2001;20:226–234
30. Carson MM, Spady DW, Beeler JA, et al. Follow-up of infants given measles vaccine at 6 months of age: antibody and CMI responses to MMRII at 15 months of age and antibody levels at 27 months of age. Vaccine. 2005;23:3247–3255
31. Capozzo AV, Ramírez K, Polo JM, et al. Neonatal immunization with a Sindbis virus-DNA measles vaccine induces adult-like neutralizing antibodies and cell-mediated immunity in the presence of maternal antibodies. J Immunol. 2006;176:5671–5681
32. de Vries RD, Stittelaar KJ, Osterhaus AD, et al. Measles vaccination: new strategies and formulations. Expert Rev Vaccines. 2008;7:1215–1223
33. Mossong J, Muller CP. Modelling measles re-emergence as a result of waning of immunity in vaccinated populations. Vaccine. 2003;21:4597–4603
34. Gagneur A, Pinquier D. Early waning of maternal measles antibodies: why immunization programs should be adapted over time. Expert Rev Anti Infect Ther. 2010;8:1339–1343
35. Steffens I, Martin R, Lopalco P. Spotlight on measles 2010: measles elimination in Europe - a new commitment to meet the goal by 2015. Euro Surveill. 2010;15:pii: 19749