A total of 4056 confirmed measles cases were reported in the United States during 2001–2022, among whom 2799 (69%) were unvaccinated, 258 (6%) had received 1 dose of a measles-containing vaccine, 217 (5%) had received ≥2 doses, and 782 (19%) had unknown vaccination status; the median age for these 4 groups was 5 (interquartile range [IQR]: 1‒14), 11 (IQR: 2‒34), 23 (IQR: 18‒30), and 34 (IQR: 24‒45) years, respectively (Table 1). Among case patients aged ≤15 months, 16 months–19 years, and ≥20 years, 2%, 11%, and 18% had received ≥1 doses of a measles-containing vaccine, respectively. Rash was reported in 86% cases (median rash duration, 5 days), fever in 84% cases, and cough, coryza, and/or conjunctivitis in 77% cases. Thirty-seven percent of cases had at least 1 complication, with diarrhea (20%) and otitis media (11%) being the most frequently reported. Eighteen percent of cases were hospitalized (median hospital stay, 4 days), and 3 deaths were reported (1 unvaccinated, one 1-dose vaccinated, and 1 with unknown vaccination status) (Table 1).

Among 3274 (81% of 4056) with available information on both vaccination status and age, we observed a general decline in full measles symptomatology and in severe outcomes with an increase in the number of doses received (Table 2, Supplementary Figure 1). Adjusting for age, we found a significantly lower odds of a classic measles presentation (OR 0.35, 95% CI, .25–.50), rash and fever (OR, 0.22; 0.12–0.41), cough, coryza, and/or conjunctivitis (OR, 0.17; 0.11–0.26), complications (OR, 0.39; 0.26–0.57), hospitalization (OR, 0.33; 0.20–0.53), and severe disease (OR, 0.52; 0.33–0.80) among case patients with ≥2 doses of a measles-containing vaccine compared to case patients with 0 doses. Classic measles presentation and having complications were significantly associated with receipt of 1 dose of a measles-containing vaccine (Figure 1). We also observed a general trend of fewer complications, hospitalizations, and severe disease among children and adults aged 5–19 years compared to younger and older age groups (Table 3). Adjusting for vaccination status, case patients aged <12 months, 12 months–4 years, and ≥20 years had significantly higher odds of complications, hospitalization, and severe disease compared to case patients aged 5–19 years (Figure 1). Similar trends in disease symptomatology and severity based on vaccination status and age were observed when restricting the analyses to those with real-time polymerase chain reaction (RT-PCR)–confirmed measles, epidemiologic-linkage, age ≥12 months, 0 doses, and within age-groups (Supplementary Tables 1–4).

Of the 475 measles cases who were reported to have received at least one dose of a measles containing-vaccine, 93 had avidity testing results available: 11 (12%) were classified as PVF and 76 (82%) as SVF (Figure 2). Individuals with SVF were older than those with PVF; median age of 29 years (IQR: 22–35 years) and 21 years (IQR: 2–29 years), respectively. The proportion of measles cases with a classic measles presentation, complications, hospitalization, and severe disease were generally higher among those with PVF compared to SVF (Table 4).

Among the 76 measles cases with SVF, 67 had PRN results available: 24 (36%) had a PRN <40 000 mIU/mL and 43 (64%) had a PRN ≥40 000 mIU/mL (Figure 2). Overall, the clinical presentation and severity of measles was similar between measles cases with SVF and a high PRN compared to those with SVF regardless of PRN results.

Measles vaccines are highly effective at preventing measles and are generally thought to provide lifelong protection to almost all vaccinees [2, 23]. Yet, vaccine failures occasionally occur, particularly with intense exposure, with breakthrough cases primarily reported in households, hospitals, and other congregate settings [24–29]. In elimination settings, decreases in the proportion of measles cases who are vaccinated has been suggested as a marker for lower vaccination rates and declining measles control, since the proportion of vaccinated cases is expected to rise with increasing coverage [3, 30]. We show that during the postelimination period in the United States, 11% of confirmed cases were reported among vaccinated persons, similar to findings from earlier postelimination years (12.8%) [6].

One third of breakthrough measles cases among persons with 2 MMR doses were reported to lack classic measles symptoms, with breakthrough cases most often missing coryza, cough, or conjunctivitis. These findings highlight the importance of keeping a high suspicion for measles among all febrile patients with rash, including vaccinated persons with a known exposure to measles. Differences in the presence of fever and rash between vaccinated and unvaccinated cases were less pronounced, and only statistically different when comparing twice-vaccinated versus unvaccinated cases; such differences are difficult to assess with this surveillance dataset because the clinical criteria used in the Council of State and Territorial Epidemiologists measles case definition requires the presence of at least fever and rash. Because of the potential for a modified clinical presentation, the clinical diagnosis of breakthrough measles cases is challenging, and studies that capture the full spectrum of symptoms associated with these infections are needed to inform recommendations for appropriate laboratory testing when measles is suspected in previously vaccinated persons. Although the current clinical criteria (at a minimum fever and rash) might not be capturing all measles infections in previously vaccinated persons, the U.S. experience of short chains of transmission despite continued importations [1] indicates that the most epidemiologically relevant infections are being identified, and that in a context of high population immunity, elimination can be sustained with current case definitions.

Breakthrough measles cases tended to have lower rates of complications, with the least severe disease among twice-vaccinated persons, underscoring the value of receipt of a full series of MMR in preventing severe illness. Prior studies have also noted breakthrough infections to have milder presentations [15, 22, 29, 31]. We thought it would be important to also account for age, which affects both vaccination status and disease severity. Confirming prior observations of higher disease severity at the extremes of age [17, 23], we show disease severity to be lowest in the 5- to 19-year-old group, with higher rates of complications and hospitalization among infants, young children, and adults. Importantly, we found that the effect of the vaccine on the presence of classic measles symptoms and disease severity persisted when controlling for age, as did the effect of age on disease severity when controlling for vaccination. In addition, similar trends in symptomatology and disease severity were observed when infants, who are more likely to be unvaccinated and to have more severe disease, were excluded from the analyses, and when the analyses of age was restricted to only those who were unvaccinated.

Although not examined in these analyses, measles transmission has been reported from breakthrough measles cases. Both direct observations [15, 29, 31, 32] and modeling studies [18] suggest that the risk of transmission from breakthrough cases is much lower compared to that from unvaccinated cases. This lower risk of transmission from vaccinated persons might be related to milder disease and lower levels of virus shedding [29, 33]. A higher likelihood of vaccinated persons to have contacts who are vaccinated (ie, clustering) might also play a role in certain settings [18]. Because of the potential for onward transmission, breakthrough measles cases in the United States are reported and managed in the same manner as unvaccinated cases including standard laboratory confirmation [34]. Stringent case management is important because there might be delays in confirming the vaccination status of cases, or the vaccination status might remain unknown. In addition, IgG avidity and PRN testing are only available at specialized laboratories, which increases the turnaround time of these tests. Therefore, rapid classification of a vaccinated case as PVF or SVF is often not possible.

Among a subset of 93 breakthrough cases with avidity testing, the majority were categorized as having SVF (82%) as opposed to PVF (12%), which was not unexpected. In settings with high 2-dose measles vaccine coverage, only a small proportion (<10%) of children will not develop protective immunity after the first dose, and 95% of these children will respond to the second dose, so at baseline, the majority of vaccinated persons would have developed antibodies against measles. Distinguishing between PVF and SVF was useful in further confirming that vaccinated cases with laboratory evidence of a prior immune response to measles had a milder presentation compared to vaccinated cases in whom laboratory evidence indicated they were naïve to measles. Although the number of PVF cases in this study was small, our results suggest that their clinical presentation might be closer to that of unvaccinated cases, implying their transmission potential might also be similar, but this needs to be investigated further.

Several limitations should be considered. Complete clinical information and vaccination status was unavailable for 19% of cases, so we limited our assessment of the effect of vaccination status on the clinical presentation and severity of measles to cases with nonmissing data. If underreporting of classic symptoms and of severe outcomes were more common with vaccinated compared to unvaccinated cases, this could have biased our analyses. However, our evaluation of PVF versus SVF (excluding unvaccinated cases) also showed more incomplete symptomatology and declining severity in persons with prior immunity versus those without prior immunity, and our results are consistent with prior studies evaluating vaccine failures. Approximately 19% of measles cases were reported to have no or unknown rash or fever, and technically would not meet the case definition for measles. These patients were classified as confirmed cases by local and state health departments, and missing information on fever or rash could be related to incomplete data transmission to CDC, or incomplete ascertainment during case investigations. Occasionally, cases lacking fever or rash are reported as confirmed when testing results are positive. Ninety-five percent of cases with no rash or fever and 68% of cases with unknown rash or fever had laboratory confirmation of measles infection in our dataset. Hospitalization may not always be an indicator of disease severity because cases may be admitted for diverse reasons (observation, diagnostic workup, isolation, underlying medical condition), and based on the provider’s level of comfort managing measles. Because the measles vaccine is highly effective at preventing measles, it is possible that some vaccinated persons might have been misdiagnosed as having measles. However, confirmation of measles in the United States requires either an epidemiological link to an infectious case, or laboratory confirmation of disease. Restricting our analyses to epidemiologically linked cases and to cases confirmed by measles RT-PCR showed similar results (Supplementary Table 1). Unvaccinated persons might have been given post-exposure prophylaxis (vaccine or immunoglobulin), which we did not account for, but this would have lessened their disease severity, and we still saw differences in disease severity by vaccination status.

Based on data from more than 4000 measles cases reported in the United States in the past 22 years, we found that both receipt of MMR vaccine and age were independently associated with the severity of measles; measles was generally more severe among unvaccinated persons (compared to vaccinated cases) and at the extremes of age. We also demonstrate the scarcity of PVFs in a setting with high 2-dose measles vaccine coverage. These findings highlight that in the rare instance in which the vaccine does not prevent measles, measles vaccine receipt can prevent severe clinical outcomes associated with measles. Because measles antibodies have been shown to wane slowly over time [35], questions remain about whether this could lead to increases in measles susceptibility and measles transmission from vaccinees in the future. Thus, as vaccinated cohorts continue to age in elimination settings, continued monitoring of vaccine failures and of possible sustained transmission among vaccinated populations is warranted. This is of relevance as long as global measles elimination targets remain unmet and measles importation risk persists.