What’s going on with measles?

ABSTRACT

Measles is a highly transmissible systemic viral infection associated with substantial mortality primarily due to secondary infections. Measles induces lifelong immunity to reinfection but loss of immunity to other pathogens. An attenuated live virus vaccine is highly effective, but lapses in delivery have resulted in increasing cases worldwide. Although the primary cause of failure to control measles is failure to vaccinate, waning vaccine-induced immunity and the possible emergence of more virulent virus strains may also contribute.

INTRODUCTION

Measles cases are again increasing globally and in the United States following a dramatic decline in reported cases during the coronavirus disease 2019 (COVID-19) pandemic. In 2019, just before the pandemic, the reported number of measles cases more than doubled to 541,401 cases globally after averaging approximately 208,000 cases per year from 2016 to 2018 (Fig. 1) (1), albeit reported measles cases represent only a fraction of the true number of cases. In the United States, 1,274 measles cases were confirmed in 2019, the most measles cases in the country since 1992 (2). However, during the COVID-19 pandemic, the reported number of measles cases declined to historic lows. Only 59,619 measles cases were reported globally in 2021 (1), and only 13 measles cases were confirmed in the United States in 2020 (2), most likely attributable to restrictions on travel, social distancing, and the personal protective measures put in place to limit the respiratory spread of severe acute respiratory syndrome coronavirus 2. Measles surveillance systems were disrupted, perhaps also contributing to the low reported number of cases. But measles cases have steadily increased since then, with 322,216 reported measles cases globally in 2023 (1). As of July 11, 2024, 167 measles cases have been reported in the United States, far exceeding the annual total of 58 cases in all of 2023 (2).

Fig 1.

Measles case distribution by month and WHO Region (2019–2024)(1).

Importantly, the COVID-19 pandemic also disrupted routine immunization services in many countries and delayed measles and rubella vaccination campaigns. According to the World Health Organization and United Nations International Children's Emergency Fund, an estimated 23 million children missed routinely administered vaccines in 2020, 3.7 million more than those in 2019. In the United States, vaccination coverage decreased by approximately one percentage point among children in kindergarten in the 2020–2021 school year compared to the prior year, representing more than 40,000 children (3).

This resurgence of measles is once again drawing attention to the disease. Kenneth Maxcy, a virologist and Chair of the Department of Epidemiology at the Johns Hopkins School of Hygiene and Public Health from 1938 until 1954, wrote “the simplest of all infectious diseases is measles.” However, despite its apparent simplicity, there is still much to learn about measles virus, its impact on the immune system, and the diseases it causes. We review our current understanding of measles epidemiology, evidence for evolution of the virus, and vaccine efficacy.

MEASLES

Measles is a highly contagious, acute illness characterized by fever and rash caused by infection with measles virus (4). Measles virus is most often transmitted by respiratory droplets over short distances but can also be transmitted through small particle aerosols that remain suspended in the air for several hours. Illness begins with fever, cough, coryza, and conjunctivitis, often associated with small white papules on the buccal mucosa called Koplik’s spots that are specific for measles and precede the rash. The characteristic rash of measles is an erythematous, maculopapular rash that begins on the head and neck and spreads to the trunk and extremities. The incubation period for measles is approximately 12.5 days (95% CI 11.8 to 13.3 days) from the time of infection to the onset of rash (5). Infected individuals are thus contagious before the illness is recognized, hampering the ability to contain outbreaks through isolation of infectious persons.

Measles is a systemic viral infection and can result in complications affecting multiple organ systems. Pneumonia accounts for most morbidity and mortality and can be due to the measles virus itself, resulting in a giant cell pneumonitis, or to secondary bacterial infection. Three rare but serious neurologic conditions are associated with measles (6). Acute disseminated encephalomyelitis is a demyelinating autoimmune disorder induced by measles virus occurring in approximately 1 in 1,000 cases (7). Measles inclusion body encephalitis results from measles virus infection of the brain in persons with impaired cell-mediated immunity (8). Subacute sclerosing panencephalitis is a rare, progressively fatal neurologic condition resulting from defective measles virus replication in the brain that occurs several years after acute infection, with an incidence of 5 to 10 per 100,000 cases of measles (9). Measles was a common cause of child mortality, estimated to have caused several million deaths each year globally before widespread vaccination and improvements in nutrition and medical care. Remarkable progress has been made in reducing measles incidence and mortality, but measles still causes 100,000 to 200,000 deaths annually, mainly in children (10).

A common laboratory method for diagnosing measles is detection of measles virus-specific IgM antibodies in serum or plasma, levels of which increase several days after rash onset (11, 12), although an increasing number of laboratories are using molecular methods that allow for earlier diagnosis and genotyping. Measles virus can be isolated in tissue culture from peripheral blood mononuclear cells, respiratory tract secretions, and urine, but the ability to isolate measles virus diminishes after rash onset as viremia decreases in response to host immune responses. Amplification and detection of measles virus RNA by reverse transcription-polymerase chain reaction (RT-PCR) from blood, urine, and nasal discharge is highly sensitive in detecting measles virus RNA and allows sequencing of the measles virus genome for molecular epidemiologic studies (13). The management of patients with measles consists of supportive therapy with hydration and nutritional supplementation, prompt antibiotic treatment of secondary bacterial infections, and vitamin A (14). Measles can be prevented through two doses of attenuated measles virus vaccine.

MEASLES VIRUS

The measles virus belongs to the genus Morbillivirus of the family Paramyxoviridae and is closely related to the viruses that cause canine and phocine distemper, the eradicated rinderpest of cattle, peste des petits ruminants of goats and sheep, and morbilliviruses of aquatic mammals. However, the measles virus is pathogenic only for primates.

The measles virus is an enveloped, non-segmented, single-stranded, negative-sense RNA virus with a genome of approximately 16,000 nucleotides. The measles virus genome encodes six structural proteins: F (fusion), H (hemagglutinin), L (large), M (matrix), N (nucleoprotein), and P (phosphoprotein). Three proteins, N, P, and L, are complexed with the measles virus RNA. Viral nonstructural proteins C and V inhibit the host innate response and regulate viral transcription and replication (15). Three proteins are associated with the viral envelope: the matrix protein, a non-glycosylated protein associated with the inner lipid bilayer, and the two surface glycoproteins, hemagglutinin and fusion. The H glycoprotein is involved in attachment of the virus to host cells, and the F glycoprotein facilitates viral fusion with the host cell membrane and is involved in the spread of measles virus from one cell to another, in part, through the formation of multinucleated giant cells (16).

Because macaques develop a disease very similar to human measles, investigations aimed at understanding the immunopathogenesis of measles have focused on experimentally infected macaques as well as naturally infected children (17–19). Measles virus enters cells through several known cellular receptors (20). Wild-type measles virus primarily enters cells by binding the signaling lymphocyte activation molecule (SLAM; CD150).(21). CD150 is a membrane glycoprotein expressed on activated T and B lymphocytes, activated monocytes, immature thymocytes, and mature dendritic cells, accounting for the lymphotropism and some of the immunosuppressive effects of measles virus. Nectin-4, also called poliovirus receptor-like-4 (PVRL4), is expressed on epithelial cells and facilitates measles virus transmission by allowing measles virus to spread laterally in the airway epithelium (22, 23). Measles virus uses the adherens junction protein nectin-4/afadin complex to initiate a viral membrane fusion apparatus that opens intercellular membrane pores and allows the transfer of infected cytoplasm between columnar epithelial cells (24). In this way, infectious virus in cells lining the tracheae and upper airway detach, triggering coughing and sneezing and the aerosolization of measles virus. Attenuated measles vaccine viruses can bind the complement regulatory protein CD46, which is widely distributed in primate tissues but the consequences of this interaction are unclear, and a role for CD46 in wild-type measles virus infection has not been established (25). Additional cellular receptors likely exist but have not yet been well characterized. For example, CD147 facilitates measles virus entry into epithelial and neuronal cells, potentially explaining measles virus infection of the central nervous system (26).

Although RNA viruses have high mutation rates, measles virus is remarkably antigenically monotypic, meaning that the surface proteins responsible for inducing protective immunity have largely retained their antigenic structure for decades (27). Consequently, live attenuated measles virus vaccines developed from a strain isolated in the 1950s still provide protection against currently circulating wild-type measles virus strains. This antigenic stability results from the fact that the immunodominant epitope, i.e., the hemagglutinating and noose epitope on the H protein, is located near the receptor-binding site (28). Escape from neutralizing antibodies that bind to these epitopes results in loss of receptor binding, preventing measles virus entry into cells. Measles virus evolution is thus constrained by these co-dominant H glycoprotein antigenic sites critical to binding the cellular receptors CD150 and nectin-4 (29).

Twenty-four measles virus genotypes are recognized based on a 450-base pair region of the nucleocapsid gene and are used for molecular epidemiology to track virus importations and transmission chains as well as to document measles virus elimination (13). Efforts are underway to build capacity in national and regional reference laboratories for extended window and whole-genome sequencing of measles viruses for higher resolution tracking of transmission chains (30, 31). Following global increases in measles vaccine coverage and regional elimination efforts, the number of circulating genotypes of wild-type measles virus has decreased markedly from 13 in 2002 to two in 2021 and 2022. Currently, only measles virus genotypes B3 and D8 are known to be circulating (10).

B3 has long been the predominant genotype in Africa, and a small recent epidemiologic study suggests that the increasing worldwide representation of B3 may reflect improved transmission compared with other wild-type strains (32). Both D8 and B3 were circulating during recent outbreaks in California, but B3 appeared to be more efficiently transmitted (32) and have a higher incidence of vaccine failure, hospitalization, and severe complications than D8 infections (33). In macaques, B3 is more pathogenic than C2 (34). The mechanism(s) responsible for this potentially increased virulence is not known.

MEASLES VIRUS PATHOGENESIS

Respiratory droplets and aerosols from infectious persons transmit measles virus to the respiratory tract of susceptible hosts where measles virus infects myeloid cells in the upper respiratory tract (23, 35). These infected myeloid cells migrate to regional lymphoid tissues and infect T and B lymphocytes. Infected lymphocytes and monocytes enter the blood stream, resulting in a cell-associated viremia and measles virus replication throughout lymphoid tissues. Infection of epithelial cells in the skin and submucosa of the respiratory tract is facilitated by migration of infected lymphocytes (36), and perivascular infiltration by lymphocytes and hyperemia result in the characteristic measles rash.

The measles virus enters the basolateral side (37) of epithelial cells in the upper respiratory tract and spreads laterally through intercellular pores to adjacent epithelial cells, creating multinucleated epithelial giant cells that can be detected in nasal secretions and conjunctivae at the end of the incubation period, during the prodrome, and during the first days of rash. Sloughing of cellular debris from the upper airway mucosa, including multinucleated giant cells containing infectious viral particles, induces coughing and sneezing of aerosolized respiratory droplets (38).

MEASLES VIRUS PERSISTENCE

Measles is an acute disease generally considered to be infectious 4 days before through 4 days after rash onset, coinciding with the ability to recover virus in culture from multiple sites (39). Although infectious virus is cleared quickly, recent studies show persistence of measles virus RNA for months after infection (8). Measles virus RNA can be detected in the blood, urine, and nasopharyngeal specimens for at least 3 months after natural infection in children (40, 41) and for at least 6 months after experimental infection in rhesus macaques. Viral RNA is found within lymphocytes and monocytes in both the circulation and lymph nodes (42). Persistence of measles virus RNA is associated with a multiphasic T-cell response, continued antibody maturation, and production of antibody-secreting cells indicative of ongoing stimulation of measles virus-specific immune responses long after clearance of infectious virus (43, 44).

HOST IMMUNE RESPONSES TO MEASLES VIRUS

The nonstructural viral V and C proteins effectively suppress the innate response by inhibiting interferon production (45, 46), allowing clinically silent dissemination of the virus before the onset of the adaptive immune response (45). The T-cell response is important for virus clearance, while the antibody response is highly correlated with protection from reinfection. The importance of cellular immune responses to measles virus clearance is demonstrated by the ability of children with agammaglobulinemia to recover from measles, whereas children with severe defects in T-lymphocyte function often develop progressive disease (47). Lymphocytes are activated and produce cytokines that modulate humoral and cellular immune responses to the measles virus, and the cellular immune response to the measles virus is a dynamic process, with functionally distinct subsets of measles virus-specific CD4⁺ and CD8⁺ T cells at different times following infection (48). Because dissemination of the measles virus within the host is largely mediated by direct cell-to-cell transmission (49), antibody-mediated immune responses are limited in their ability to clear infection (50, 51).

Protection from reinfection correlates best with levels of neutralizing antibodies and is a continuum. Serum levels of virus-neutralizing antibodies above 120 mIU/mL measured by a plaque-reduction neutralization assay correlate with protection from measles disease (rash), but higher levels are required to prevent infection (52, 53). Avidity, a measure of how tightly antibodies bind to target antigens, is an important characteristic of a mature antibody response, is critical to the development of protective immunity, and can be used to differentiate primary and secondary vaccine failure in persons with a history of prior measles vaccination (54).

The duration of protective immunity following wild-type measles virus infection is lifelong. Observations by Peter Panum during a measles epidemic on the isolated Faroe Islands in 1846 demonstrated the long-term protective immunity following measles (55). Two measles epidemics occurred on the islands decades apart. Adults with a history of measles during childhood did not acquire measles after re-exposure 65 years later. The mechanisms involved in long-term protective immunity to measles virus are not completely understood, but levels of measles virus-specific antibodies diminish little over time (56), and continued production is associated with persistence of viral RNA, ongoing stimulation of germinal center formation, avidity maturation, and production of virus-specific antibody-secreting cells for months (44).

MEASLES VIRUS IMMUNE SUPPRESSION

Despite an effective immune response that clears infectious virus and results in long-term protective immunity, abnormalities of both the innate and adaptive immune responses accompany measles virus infection. Transient lymphopenia occurs (57), but cell counts quickly recover and likely reflect redistribution to lymphoid tissues. Functional abnormalities are also measurable. Dendritic cells mature poorly, lose the ability to stimulate proliferative responses in lymphocytes, and undergo cell death when infected with measles virus in vitro (58, 59). Delayed-type hypersensitivity responses to recall antigens, such as tuberculin, are suppressed, and cellular and humoral responses to new antigens are impaired (60).

Measles also impacts memory immune responses to other pathogens. Measles virus infects CD150⁺ immune cells, including memory T and B lymphocytes (61, 62) with incomplete reconstitution of B-lymphocyte pools (63). Most importantly, measles results in depletion of a substantial fraction of circulating antibodies against viruses and bacteria to which an individual was previously exposed, reducing both antibody diversity and quantity (64) and resulting in what has been called “immune amnesia.”

As a consequence of these abnormalities, effective immune responses to the measles virus are associated with depressed responses to unrelated antigens (65). This state of immune suppression enhances susceptibility to secondary bacterial and viral infections and is responsible for much of the morbidity and mortality associated with measles. Epidemiological studies suggest this increased risk of secondary infections may extend for as long as 2 to 3 years (66).

MEASLES VACCINES

Enders and Peebles isolated the original (genotype A) measles virus from the blood of David Edmonston, a child with measles (67), and empirically developed a live attenuated measles vaccine (LAMV) by passage of the Edmonston virus in primary human cells followed by chick embryo fibroblasts (CEFs) to produce the Edmonston A and B viruses (68, 69). These candidate LAMVs produced no disease in macaques and provided protection from challenge with wild-type measles virus (70, 71). The LAMV licensed in 1963 frequently produced fever and rash (72, 73). Further passage in tissue culture yielded the current LAMVs that cause fever and rash in less than 10% of immunized children (74, 75). The original Edmonston strain of the measles virus is not available, and genotype A viruses are extinct (76), so it is not possible to directly compare LAMVs to the original wild-type virus from which it was derived. The earliest available virus (Edmonston “wild-type”) does not cause a rash in macaques but does produce viremia (17, 77).

LAMVs are closely related and similarly safe and effective with few sequence differences (75, 78, 79), but the mechanism(s) of attenuation is not known. LAMV sequences differ from wild-type virus in most viral proteins, any of which may contribute to attenuation. Vaccine virus attenuation results in a virus that replicates less well in lymphocytes and myeloid cells than wild-type virus but replicates similarly in primary epithelial cells and endothelial cells (80). Changes common to all LAMVs are in P/V/C (P/V-Glu225Gly, C-Ala73Val), M (Gly61Asp, Glu89Lys), H (Ser211Gly, Asn481Tyr), and L (Asp1717Ala) plus two nucleotides (26, 42) in the 3′ transcriptional control region and three nucleotides (4978, 5073, 5349) in the 5′ UTR. However, no single or combination of changes has been identified as responsible for attenuation (78, 79, 81–88). Studies of recombinant viruses using the Japanese IC-B WT and CAM-70 vaccine strains showed that M, F, H, and L all contribute to efficient growth of CAM-70 in CEFs (84, 89), but changes that alter in vivo virulence have not been identified.

Measles vaccines induce humoral and cellular immune responses similar to wild-type measles virus infection, but the response to measles vaccine is less robust than the response to wild-type infection with lower and less sustained levels of antibody, although cellular responses are similar (90).

Measles vaccines are typically combined with other live attenuated virus vaccines, such as rubella (MR), mumps (MMR), and varicella (MMRV). The proportion of children who develop protective antibody levels following measles vaccination depends on the presence of inhibitory maternal antibodies and the immunological maturity of the child. In general, 85% to 90% of children develop protective antibody levels when given one dose of measles vaccine at 9 months of age, and 90% to 95% respond when first vaccinated at 12 months of age. A second vaccine dose is recommended to immunize those who fail to respond to a first dose, not to boost the initial response. This second year of life platform for measles vaccination also provides another opportunity for those children who missed out on measles vaccination in the first year of life.

With time, measles virus-specific antibodies and CD4⁺ T cells induced by vaccination decrease (91–94). Secondary vaccine failure rates are estimated to be approximately 5% at 10–15 years after immunization (95, 96). A detailed study characterizing the dynamics of measles IgG antibodies in 1,505 children in China showed that children who failed to develop an antibody response after a first dose of measles vaccine (interestingly associated with cesarean section birth) responded to a second dose, but additional doses only resulted in a small increase in antibodies (97). Other studies to identify approaches to boosting waning measles immunity have shown that a third dose of LAMV increases immunity only transiently (98), probably because LAMV replication required for immune stimulation is neutralized by even small amounts of pre-existing antibodies. Therefore, a different type of vaccine designed to stimulate an immune response in the face of pre-existing antibodies will be required for this purpose—most likely recombinant H and F protein that reflect the measles virus strain(s) in circulation. Such vaccines are in development.

Modeling studies of deaths averted due to immunization show that measles vaccines account for the highest proportion of deaths averted compared to any other vaccine—approximately 20% of all deaths averted (99). Although transmission has occurred within a vaccinated population, there is currently no evidence that this is an important contributor to the failure to control measles. However, this balance could be shifted in the future.

MEASLES ELIMINATION AND ERADICATION

The World Health Organization defines measles elimination as the absence of endemic measles virus transmission in a defined geographical area (e.g., region or country) for at least 12 months in the presence of a well-performing surveillance system. Thus, measles elimination does not mean the total absence of cases as measles virus importations may occur with limited transmission chains. Measles elimination is a fragile state that requires continued resources and efforts to sustain, and elimination status can be lost. Measles eradication is defined as reduction of the global incidence of measles to zero as a result of deliberate efforts, with no more risk of reintroduction obviating the necessity for further control measures.

Measles meets the criteria for a disease that can be eradicated: (i) there is no animal or environmental reservoir, and humans are critical to maintaining transmission; (ii) accurate diagnostic tests are available; (iii) measles vaccines and existing vaccination strategies are effective and safe; and (iv) measles virus transmission has been interrupted in a large geographic area (e.g., nationwide) for a prolonged period (100).

The World Health Organization conducted a comprehensive assessment of the feasibility of measles and rubella eradication (101). This assessment proposed that a time-bound measles eradication goal should only be set when substantial and measurable progress has been made, and the strategies, resources, and commitment are likely to be in place to interrupt the final transmission pathways. The endgame would comprise a time-limited (e.g., 5 years) intensification of efforts with a realistic chance of achieving eradication by the target date. Many experts agree there are risks to delaying eradication because of the changing epidemiology that may make it increasingly more difficult (102, 103), as well as strong ethical, economic, and epidemiological justifications for urgently achieving measles and rubella eradication (104, 105).

WHAT’S GOING ON WITH MEASLES?

Measles cases are again increasing globally and in the United States following historically low numbers of reported cases during the COVID-19 pandemic but have not yet risen to the levels seen in 2019. Measles outbreaks will continue to occur as long as clusters of susceptible individuals exist, and infectious individuals move into and out of these communities. Although much is known about measles and the measles virus, there is still much to be learned, including the duration and consequences of the loss of memory B and T cells, the importance of waning immunity for measles elimination and eradication goals, and the potential for the virus to evolve. Our currently used attenuated measles vaccines are highly safe and effective, but new vaccines and diagnostics would help achieve a world without measles.

FUNDING

The authors received no funding for this work.