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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Joseph Nasr, M.D.[2]; Guillermo Rodriguez Nava, M.D. [3]; Yamuna Kondapally, M.B.B.S[4];

## Early descriptions and Discovery

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* Classical descriptions: Reports of measles predate the Common Era; the first scientific description of the disease and its distinction from smallpox is attributed to the Persian physician Ibn Razi (Rhazes) (860-932A.D.) in a book entitled "Smallpox and Measles" (in Arabic: Kitab fi al-jadari wa-al-hasbah).
* 18th-19th century milestones: A Scottish physician, Francis Home, demonstrated in 1757 that measles was caused by an infectious agent present in the blood of patients.
* Virus isolation (modern era): In 1954, the measles virus was isolated from an 11-year-old boy from the US, David Edmonston, and adapted and propagated on a chick embryo tissue culture in Boston, Massachusetts, by John F. Enders and Thomas C. Peebles. The Edmonston isolation was the seed for vaccine development[1].

## Development of Treatment Strategies

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* Pre-Vaccine Disease Burden (U.S.): Before the measles vaccine, nearly all children contracted the virus by age 15; annually, approximately 549,00 reported cases and 495 deaths; around 48,000 hospitalizations, 7,000 seizures, and about 1,000 permanent disabilities from encephalitis (brain damage or deafness)[2].
* First U.S. licensure (1963): The Edmonston B live-attenuated vaccine (Rubeovax, Merck) was licensed in 1963; later withdrawn in 1975 due to reactogenicity. It was further attenuated to yield Edmonston-Enders (Moraten) and Edmonston-Zagreb (EZ) strains[1].
* Inactivated vaccine (1963): Licensed in parallel with Edmonston B, but withdrawn in 1967 due to lack of protection. Recipients often developed atypical measles if exposed to wild-type virus[3].
* Schwarz strain (1965): Introduced as a further-attenuated vaccine; no longer used in the United States[1].

* Edmonston-Enders strain (1968): Licensed as a further-attenuated vaccine; caused fewer reactions than Edmonston B[1].
* Current U.S. use: Only the Edmonston-Enders strain (Moraten) remains in use, incorporated into MMR or MMRV (ProQuad). No single-antigen measles vaccine is available in the U.S[1].

* Formulation: Vaccines are prepared in chick embryo fibroblast cultures; supplied as freeze-dried powder with stabilizers (human albumin, neomycin, sorbitol, gelatin).

* Additional strains (Global): The Schwarz strain (derived from Edmonston A; genetically identical to Moraten) is a component of MMR (Priorix®, GSK), licensed in 1997 and used in >100 countries. AIK-C (Japan) is licensed as mono- and MR-combination vaccine in Japan, Vietnam, and Iran[1][4].
* Non-Edmonston Strains: Leningrad-4, Shanghai-191, Chang-47, CAM-70 have been licensed/used regionally (Russia, China, South Africa)[4].
* Effectiveness & Safety (summary): Dose-1 Effectiveness ≈ 84% (12mo) and 92.5% (≥ 12mo); ~94% after two doses; serious adverse events are rare across licensed strains[5].

## U.S. Elimination, Importations, and Regional Certification

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* U.S. elimination (2000): Endemic transmission ceased in 2000 (definition: ≥12 months without endemic transmission with robust surveillance)[6].
* Americas certification: Region of the Americas declared measles-free on September 27, 2016.

* Ongoing importations: Despite elimination, U.S. cases continue annually due to importations and spread in under-vaccinated communities; frequent sources have included England, France, Germany, India, Philippines, among others[7][8][9][10].
* Current resurgence: By May 30, 2025, there were 1,088 confirmed U.S. cases and 3 deaths; ~96% were unvaccinated/unknown vaccination status, and 12% were hospitalized. If transmission continues for >12 months, the U.S. will lose its measles elimination status[10].

## Scientific Inflection Points (receptors, immune amnesia)

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* Receptor biology: Measles virus recognizes CD46, SLAM/CD150, and nectin-4. Wild-type virus primarily uses CD150 (lymphocytes) and nectin-4 (epithelial cells), while vaccine strains use CD46. Discovery of SLAM and nectin-4 in 2010–2011 clarified lymphocyte tropism and epithelial exit/transmission[11][12][13][14].
* Mechanism of immune suppression: Wild-type MeV preferentially infects CD150^hi memory T cells and also infects naïve and memory B cells, leading to depletion and reshaping of preexisting immunity. This immune amnesia diminishes antibody repertoires and alters B-cell diversity, persisting for 5–12 months post-infection[15][16][17][18][19][20][21][22].
* Loss of prior vaccine protection: Children with prior measles may lose protective antibody levels to other vaccines, e.g., tetanus, highlighting the broad impact of immune amnesia[23].
* Innate immune amnesia: MeV also induces apoptosis in MAIT cells, weakening first-line mucosal defenses and further increasing vulnerability to secondary infections[24].

* Contrast with vaccine strains: Attenuated measles vaccines do not cause immune amnesia. Instead, they induce trained immunity, with epigenetic reprogramming of γδ T cells that enhances non-specific defenses against other pathogens[25][26][27][28][29][30].

## Antigenic Stability, Genotypes, and Why the Classic Vaccines Still Work

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* Genotype history: WHO has defined 24 genotypes (based on the 450-bp N-gene window). Since 2018, global circulation has been limited to B3, D4, D8, and H1. As of 2024–2025, B3, D8, and H1 are the dominant strains in ongoing outbreaks[31].
* Surface glycoproteins: The hemagglutinin (H) and fusion (F) proteins—major neutralizing antibody targets—have remained antigenically stable for decades. A key immunodominant epitope on H overlaps the SLAM-binding domain, which means mutations that escape neutralization often also reduce receptor binding and viral fitness[32][33][34].
* Vaccine cross-protection: Current vaccines, all derived from genotype A (Edmonston lineage), still provide robust protection against these circulating wild-type genotypes[33].
* Monoclonal antibody monitoring: A D4.2 sub genotype has shown reduced binding by some neutralizing monoclonals at major H epitopes, but clinical vaccine escape has not been documented. Ongoing sequencing is monitoring such variants[35].
* Genomic surveillance advances: Low-cost Nanopore full-genome sequencing is increasingly used to track transmission chains and to watch for potential vaccine-escape variants[36].

## Resurgence Era (2019 → 2024–2025)

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* 2019 global surge: Reported measles cases increased from 132,490 (2016) to 869,770 (2019), fueled by major outbreaks in the Democratic Republic of Congo, Madagascar, Samoa, Ukraine, and Brazil. NEJM highlights vaccine hesitancy as a central driver, alongside inequitable access[7].
* Pandemic shock: COVID-19 pandemic disruptions pushed global MCV1 coverage down to 81%—the lowest since 2008. By 2022–2023, coverage had only partially recovered to 83%, leaving large immunity gaps[37].
* 2024–2025 outbreaks:
* Global scale: In 2024, WHO confirmed 395,521 laboratory-confirmed cases worldwide, and another 16,147 in the first two months of 2025. Over half of reported patients were hospitalized, indicating an underestimation of the true burden[38].
* Europe: Recorded its highest measles case count in more than 25 years in 2024, accounting for ~20% of global cases[38].
* United States: As of May 30, 2025, there were 1,088 confirmed cases and 3 deaths; ~96% were in unvaccinated or unknown-status individuals, and 12% required hospitalization. NEJM warns that if continuous transmission persists for >12 months, the U.S. will lose its elimination status[2].
* Policy headwinds: NEJM notes that U.S. withdrawal of financial support from WHO (≈19% of its budget) and Gavi (≈13%) threatens global measles control and domestic health security.

## Policy Context

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* 1987 – Vitamin A policy: WHO/UNICEF issued a landmark statement on vitamin A supplementation for measles, based on trial evidence that supplementation reduced complications and mortality[39].
* 1998 – Measles Partnership: The Measles Partnership (later Measles & Rubella Initiative) was established by WHO, UNICEF, CDC, UN Foundation, and the American Red Cross to accelerate global control[6].
* 2000 – Two-dose policy: WHO adopted the two-dose measles vaccination schedule for all children, to achieve and sustain elimination[6].
* 2012 – Global Vaccine Action Plan (GVAP): Set measles elimination goals across all WHO regions by 2020 (not achieved)[6].
* 2017 – WHO “Immunization Agenda 2030” (IA2030): Established elimination targets through 2030[6].
* 2025 – Policy headwinds: According to the New England Journal of Medicine (NEJM), U.S. withdrawal of support from WHO (≈19% of its budget) and Gavi (≈13%), which undermines global measles control capacity and threatens U.S. health security[40].

## Impact on Cultural History

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* Pre-vaccine burden (United States)[41]:
* Before the introduction of a live measles vaccine in 1963, nearly all children contracted measles by age 15.
* Each year: an average of 549,000 reported cases and 495 deaths, though the true annual burden was closer to 3–4 million infections.
* Of reported cases, ~48,000 were hospitalized, 7,000 experienced seizures, and ~1,000 developed chronic disability from measles encephalitis.
* Dramatic reduction after vaccination[6]:
* Vaccine introduction and scale-up led to a >99% decline in U.S. measles cases compared with the pre-vaccine era.
* Measles was declared eliminated in the U.S. in 2000, defined as the absence of endemic transmission for ≥12 months with high-quality surveillance.
* Global control milestones:
* The WHO Expanded Programme on Immunization (EPI) adopted measles vaccine in 1977, marking it as a global public health priority.
* The Region of the Americas was declared measles-free by PAHO/WHO on September 27, 2016.
* Persistent global burden:
* Measles remains a leading cause of vaccine-preventable childhood death globally despite progress[6].
* In 2024, WHO confirmed 395,521 laboratory-confirmed cases worldwide, with another 16,147 cases in the first 2 months of 2025[38].
* Over 50% of reported patients were hospitalized, meaning the true burden is substantially undercounted.
* Importations and outbreaks in the U.S.[42][43]:
* Between 2000–2013, the U.S. recorded 37–220 cases annually, largely due to importations from measles-endemic regions and spread in under-vaccinated communities.
* In recent years, importations often originated from England, France, Germany, India, and the Philippines.
* By May 30, 2025, the U.S. had 1,088 confirmed cases and 3 deaths, with 96% of cases in un/unknown-vaccinated individuals and 12% hospitalized. If transmission persists beyond 12 months, the U.S. will lose its elimination status.

## References

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1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Orenstein, W.A. et al. (2023) Plotkin’s vaccines. 8th ed. Philadelphia, PA: Elsevier - Health Sciences Division.
2. ↑ 2.0 2.1 CDC (2025) Measles Cases and Outbreaks, Measles (Rubeola). Available at: https://www.cdc.gov/measles/data-research/index.html (Accessed: September 19, 2025).
3. ↑ Polack, F.P. (2007) “Atypical measles and enhanced respiratory syncytial virus disease (ERD) made simple,” Pediatric research, 62(1), pp. 111–115. Available at: https://doi.org/10.1203/PDR.0b013e3180686ce0.
4. ↑ 4.0 4.1 WHO Immunization Data portal - All Data (no date) Immunization Data. Available at: https://immunizationdata.who.int/global (Accessed: September 19, 2025).
5. ↑ Uzicanin, A. and Zimmerman, L. (2011) “Field effectiveness of live attenuated measles-containing vaccines: a review of published literature,” The journal of infectious diseases, 204 Suppl 1(suppl_1), pp. S133-48. Available at: https://doi.org/10.1093/infdis/jir102.
6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Do, L.A.H. and Mulholland, K. (2025) “Measles 2025,” The New England journal of medicine [Preprint], (NEJMra2504516). Available at: https://doi.org/10.1056/NEJMra2504516.
7. ↑ 7.0 7.1 Patel, M.K. et al. (2020) “Progress toward regional measles elimination - worldwide, 2000-2019,” MMWR. Morbidity and mortality weekly report, 69(45), pp. 1700–1705. Available at: https://doi.org/10.15585/mmwr.mm6945a6.
8. ↑ Hotez, P.J., Nuzhath, T. and Colwell, B. (2020) “Combating vaccine hesitancy and other 21st century social determinants in the global fight against measles,” Current opinion in virology, 41, pp. 1–7. Available at: https://doi.org/10.1016/j.coviro.2020.01.001.
9. ↑ Rader, B. et al. (2025) “Revising US MMR vaccine recommendations amid changing domestic risks,” JAMA: the journal of the American Medical Association, 333(14), pp. 1201–1202. Available at: https://doi.org/10.1001/jama.2025.3867.
10. ↑ 10.0 10.1 CDC (2025) Measles Cases and Outbreaks, Measles (Rubeola). Available at: https://www.cdc.gov/measles/data-research/index.html (Accessed: September 19, 2025).
11. ↑ Dörig, R.E. et al. (1993) “The human CD46 molecule is a receptor for measles virus (Edmonston strain),” Cell, 75(2), pp. 295–305. Available at: https://doi.org/10.1016/0092-8674(93)80071-l.
12. ↑ Naniche, D. et al. (1993) “Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus,” Journal of virology, 67(10), pp. 6025–6032. Available at: https://doi.org/10.1128/JVI.67.10.6025-6032.1993.
13. ↑ Tatsuo, H. et al. (2000) “SLAM (CDw150) is a cellular receptor for measles virus,” Nature, 406(6798), pp. 893–897. Available at: https://doi.org/10.1038/35022579.
14. ↑ Mühlebach et al. (2011) “Adherens junction protein nectin-4 is the epithelial receptor for measles virus,” Nature, 480(7378). Available at: https://doi.org/10.1038/nature10639.
15. ↑ Condack C, Grivel JC, Devaux P, Margolis L, Cattaneo R. Measles virus vaccine attenuation: suboptimal infection of lymphatic tissue and tropism alteration. J Infect Dis. 2007;196(4):541-9
16. ↑ de Vries RD, McQuaid S, van Amerongen G, Yuksel S, Verburgh RJ, Osterhaus AD, et al. Measles immune suppression: lessons from the macaque model. PLoS Pathog. 2012;8(8):e1002885
17. ↑ Laksono BM, Grosserichter-Wagener C, de Vries RD, Langeveld SAG, Brem MD, van Dongen JJM, et al. In Vitro Measles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells. J Virol. 2018;92(8).
18. ↑ Laksono BM, de Vries RD, Verburgh RJ, Visser EG, de Jong A, Fraaij PLA, et al. Studies into the mechanism of measles-associated immune suppression during a measles outbreak in the Netherlands. Nat Commun. 2018;9(1):4944.
19. ↑ Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, et al. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science. 2019;366(6465):599- 606.
20. ↑ Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L, Parker E, et al. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol. 2019;4(41).
21. ↑ Mina MJ, Metcalf CJ, de Swart RL, Osterhaus AD, Grenfell BT. Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science. 2015;348(6235):694-9.
22. ↑ Buhl D, Staudacher O, Santibanez S, Rossi R, Girschick H, Stephan V, et al. Specifically Increased Rate of Infections in Children Post Measles in a High Resource Setting. Front Pediatr. 2022;10:896086.
23. ↑ Ashbaugh HR, Cherry JD, Hoff NA, Doshi RH, Mukadi P, Higgins SG, et al. Reported History of Measles and Long-term Impact on Tetanus Antibody Detected in Children 9-59 Months of Age and Receiving 3 Doses of Tetanus Vaccine in the Democratic Republic of the Congo. Pediatr Infect Dis J. 2023;42(4):338-45
24. ↑ Haeryfar SMM. On invariant T cells and measles: A theory of "innate immune amnesia". PLoS Pathog. 2020;16(12):e1009071.
25. ↑ Mina MJ. Measles, immune suppression and vaccination: direct and indirect nonspecific vaccine benefits. J Infect. 2017;74 Suppl 1:S10-S7.
26. ↑ Sorup S, Benn CS, Stensballe LG, Aaby P, Ravn H. Measles-mumps-rubella vaccination and respiratory syncytial virus-associated hospital contact. Vaccine. 2015;33(1):237-45.
27. ↑ Aaby P, Martins CL, Garly ML, Bale C, Andersen A, Rodrigues A, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010;341:c6495.
28. ↑ Arts RJW, Carvalho A, La Rocca C, Palma C, Rodrigues F, Silvestre R, et al. Immunometabolic Pathways in BCG-Induced Trained Immunity. Cell Rep. 2016;17(10):2562-71.
29. ↑ Arts RJW, Moorlag S, Novakovic B, Li Y, Wang SY, Oosting M, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018;23(1):89-100 e5.
30. ↑ Roring RJ, Debisarun PA, Botey-Bataller J, Suen TK, Bulut O, Kilic G, et al. MMR vaccination induces trained immunity via functional and metabolic reprogramming of gammadelta T cells. J Clin Invest. 2024;134(7).
31. ↑ CDC. Genetic Analysis of Measles Viruses 2025 [updated 7 June 2024. Available from: https://www.cdc.gov/measles/php/laboratories/genetic-analysis.html].
32. ↑ Beaty SM, Lee B. Constraints on the Genetic and Antigenic Variability of Measles Virus. Viruses. 2016;8(4):109.
33. ↑ 33.0 33.1 Munoz-Alia MA, Nace RA, Zhang L, Russell SJ. Serotypic evolution of measles virus is constrained by multiple co-dominant B cell epitopes on its surface glycoproteins. Cell Rep Med. 2021;2(4):100225.
34. ↑ Tahara M, Ohno S, Sakai K, Ito Y, Fukuhara H, Komase K, et al. The receptor-binding site of the measles virus hemagglutinin protein itself constitutes a conserved neutralizing epitope. J Virol. 2013;87(6):3583-6.
35. ↑ Munoz-Alia MA, Muller CP, Russell SJ. Antigenic Drift Defines a New D4 Subgenotype of Measles Virus. J Virol. 2017;91(11).
36. ↑ Namuwulya P, Bukenya H, Tushabe P, Tweyongyere R, Bwogi J, Cotten M, et al. Near�Complete Genome Sequences of Measles Virus Strains from 10 Years of Uganda Country-wide Surveillance. Microbiol Resour Announc. 2022;11(8):e0060622.
37. ↑ Minta, A.A. et al. (2024) “Progress toward measles elimination - worldwide, 2000-2023,” MMWR. Morbidity and mortality weekly report, 73(45), pp. 1036–1042. Available at: https://doi.org/10.15585/mmwr.mm7345a4.
38. ↑ 38.0 38.1 38.2 Provisional monthly measles and rubella data (no date) Who.int. Available at: https://www.who.int/teams/immunization-vaccines-and-biologicals/immunization-analysis-and-insights/surveillance/monitoring/provisional-monthly-measles-and-rubella-data (Accessed: September 19, 2025).
39. ↑ World Health Organization (1987) “EXPANDED PROGRAMME ON IMMUNIZATION PROGRAMME FOR THE PREVENTION OF BLINDNESS NUTRITION : Joint WHO/UNICEF Statement on Vitamin A for measles = PROGRAMME ÉLARGI DE VACCINATION PROGRAMME DE PRÉVENTION DE LA CÉCITÉ NUTRITION : Déclaration conjointe OMS/FISE sur la vitamine A pour la rougeole,” Weekly Epidemiological Record = Relevé épidémiologique hebdomadaire, 62(19), pp. 133–134. Available at: https://iris.who.int/handle/10665/226256 (Accessed: September 19, 2025).
40. ↑ Bendavid, E. and Bhattacharya, J. (2014) “The relationship of health aid to population health improvements,” JAMA internal medicine, 174(6), pp. 881–887. Available at: https://doi.org/10.1001/jamainternmed.2014.292.
41. ↑ CDC (2024) Chapter 13: Measles, Epidemiology and Prevention of Vaccine-Preventable Diseases. Available at: https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-13-measles.html (Accessed: September 19, 2025).
42. ↑ van den Hof, S. et al. (2001) “Measles outbreak in a community with very low vaccine coverage, the Netherlands,” Emerging infectious diseases, 7(3 Suppl), pp. 593–597. Available at: https://doi.org/10.3201/eid0707.010743.
43. ↑ Woudenberg, T. et al. (2017) “Large measles epidemic in the Netherlands, May 2013 to March 2014: changing epidemiology,” Euro surveillance : bulletin Europeen sur les maladies transmissibles [Euro surveillance : European communicable disease bulletin], 22(3). Available at: https://doi.org/10.2807/1560-7917.ES.2017.22.3.30443.

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