A commentary on measles vaccine in the context of outbreaks: Viral evolution, waning immunity and public trust

ABSTRACT

The measles vaccine, introduced over 60 y ago, has been proven to be both safe and effective. Despite the genetic diversity of the measles virus, eradication is considered possible with near-complete coverage of the two-dose vaccination schedule. However, real-world data show that this level of control has not yet been achieved. In addition to outbreaks among unvaccinated individuals, increasing numbers of measles cases are occurring among fully vaccinated, seropositive individuals. Both primary and secondary vaccine failures have been documented. Reduced vaccine effectiveness may occur in people with innate immune deficiencies, immunocompromised individuals (including those with HIV), and patients with chronic conditions such as diabetes. Furthermore, in regions without circulating wild-type virus, vaccine-induced antibody levels tend to decline over time and the impact of this may be more significant among infants. Emerging evidence highlights the importance of T lymphocyte – mediated immunity on effective B cell mediated immune response. Compounding the challenge, measles vaccination and infection are politicized, undermining public trust. Given the high transmissibility of measles, its potential for presymptomatic transmission, and the absence of specific early symptoms, complete eradication may not be feasible in the near term. Nevertheless, combining vaccine advocacy, transparent communication, and ongoing research will be critical to improving global vaccination strategies and public confidence.

The measles vaccine is safe and effective, and every measles-related death is preventable.¹ A recent Nature editorial highlights the dangers of vaccine misinformation and the importance of upholding evidence-based public health policy.² As of July 9, 2025, the United States has reported 1,288 measles cases and three deaths despite strong historical vaccination efforts.³ While these numbers clearly reinforce the vaccine’s importance, primary vaccine failure with poor host innate and adaptive immune responses to measles antigens^4,5 and secondary vaccine failure with waning immunity⁵ may be contributing factors.

According to CDC surveillance data, between 2000 and 2017, 9–11% of measles cases occurred in individuals who had received two doses of the measles-containing vaccine (MCV).³ In the 2014 Micronesia outbreak, 40% of infections were documented in previously vaccinated adults.⁶ In this outbreak, cold chain maintenance of the vaccines could not be verified given the remote and tropical nature of Micronesia and could have contributed to the primary and secondary vaccine failure. Additional outbreaks in Japan⁷ and the Netherlands⁸ involved transmission among twice-vaccinated people with detectable neutralizing antibodies. In the case of the Netherlands, the cases involved healthcare workers.⁸ These cases suggest secondary vaccine failure, where immune protection wanes over time.⁴

A recent thorough review of serologic data from healthy individuals by Schenk et al. estimated the annual exponential waning rates after 2-dose measles vaccination (MMR2) to be 0.009 (0.005–0.016; I² = 85.2%).⁹ The investigators suggested that 8.6% of initially seropositive individuals would become seronegative over 10 years.⁹ Another study by LeBaron et al. from the United States tracked the measles antibody level in kindergarteners who received two doses of MMR and showed continued slow decline in measles antibody titers.¹⁰ The investigators projected that 33% of their healthy study population will have antibody levels below the protecting threshold (≤120 mIU/mL) 20 years after MMR2.¹⁰ A 2021 cohort study comparing measles immunity from natural infection versus vaccination found that only 6% of individuals with prior infection lost protective IgG within 10–15 y, compared to 20% of vaccinated individuals, suggesting that naturally acquired immunity may persist longer in some cases.¹¹ In a prospective study between 2006 and 2008, investigators studied 413 infant-mother pairs. At birth, 91.5% (95% CI: 88.8, 94.2) of infants had protective antibody levels, which declined to 26.3% (95% CI: 21.0%, 31.9) at 3 months, 3.4% (95% CI: 0.9, 5.9) at 6 months, and 2.1% (95% CI: 0.1, 4.1) at 9 months. Furthermore in 207 healthy woman-infant pairs, women vaccinated with single dose MMR (n = 87) had significantly fewer IgG antibodies [geometric mean titer 779 (95% confidence interval 581 to 1,045) mIU/ml] than did naturally immune women (n = 120) [2,687 (2,126–3,373) mIU/ml (p < .001)], and infants of vaccinated women had significantly lower antibody concentrations than did infants of naturally immune women at all ages over the follow-up period.¹² Presence of maternal antibodies endured for a median of 0.97 months for infants of vaccinated women. At 6 months of age, more than 99% of infants of vaccinated women and 95% of infants of naturally immune women had lost maternal antibodies according to the model.¹² More recent studies replicated this data and studies from premature babies showed that only 10.80% and 3.30% at preterm infants were measles seropositive at age of 3 and 6 months, respectively.¹³

There is limited data on waning of measles antibody responses in the immunocompromised individuals and those with chronic illness such as type 2 diabetes. These individuals may experience even higher rates of waning serologic immunity, especially in areas with universal measles immunization and no wild-type measles virus circulation. Recent data from HIV-infected individuals in a U.S. clinic showed that only 11.2% of 13,622 people had presumptive measles immunity.¹⁴

Current measles vaccines are based on a clade A virus developed more than 60 years ago.^15,16 However, the measles virus has at least 24 genotypes.¹⁶ The antigenic differences among genotypes have been assumed to be negligible due to genetic stability and minimal antigenic drift.¹⁷ Recent and ongoing measles outbreaks have been predominantly associated with two circulating measles virus (MeV) genotypes: genotype D8 and genotype B3, and in some regions, these strains may be circulating concurrently.¹⁸ The B3 genotype was suggested to be more transmissible than other genotypes¹⁹ and may have higher capacity to overcome vaccine-induced immunity.^20–22

In in vitro studies, mutations in H, F and M proteins were shown to be responsible for neutralization escape.²² Interestingly, these mutations were also found in subacute sclerosing panencephalitis cases.²² During outbreaks in Europe, Asia, and America, a mutation in H protein was observed in strains that belonged to B3 and D8.¹⁸

Although neutralizing antibodies are critical for measles immune responses, innate immunity and T cell immunity have also been shown to play a role in measles immunity.²³ Measles C protein functions as a virulence factor and suppresses the host innate immune responses.²³ Mutations in C protein may play a role in host immune responses during outbreaks.²⁴ Mutations in T-cell epitope regions were shown to disrupt the ability of vaccine-induced CD4⁺ T cells to respond to circulating viruses.²⁵

These findings support the need for better understanding of host-measles virus interactions and genomic surveillance during outbreaks.¹⁸ Recent studies questioned whether immunity generated by clade A vaccines fully protects against all circulating genotypes.²⁶ In some cases, breakthrough infections have occurred despite the presence of neutralizing antibodies, suggesting qualitative gaps in immune memory.²⁶ Guidelines for the screening and the management of non responders to measles vaccine are needed, in particular for high risk groups (e.g. Healthcare workers).

COVID-19 pandemic had a damaging effect on public vaccine confidence and led to a broad vaccine hesitance and decrease in vaccination rates including measles vaccine.²⁷ Public confidence in vaccines is best improved by transparency, availability of thorough data and a timely communication.²⁸ A 2022 study by Kerr et al. demonstrated that balanced messages were perceived as trustworthy as persuasive messages; however, prior beliefs had a moderating role such that balanced messages were consistently perceived as more trustworthy among those with negative or neutral prior beliefs about the message content.²⁸ Gesser-Edelsburg et al.²⁹ examined ways for health organizations to correct misinformation concerning the measles vaccination on social networks. They examined the responses of pro-vaccination and vaccine hesitant groups to two different misinformation correction approaches on social media. The health organization either provided the correct information or communicated the information transparently and addressed the public’s concerns. They observed that transparent approach that addressed the fears and emotions was most effective in both the pro-vaccination and the hesitant groups. The authors noted that pro-vaccination group is not a captive audience, and that continued efforts are needed to address public’s fears and concerns.²⁹

Measles vaccine is highly effective and safe and it prevents pneumonia, encephalitis and death.³⁰ Between 2000 and 2023, an estimated cumulative total of 60 million measles related deaths have been prevented globally by measles vaccination.³⁰ We may not be able to prevent measles outbreaks in small unvaccinated communities, and we may not be able to eradicate measles globally but we can advocate for genomic measles surveillance and precision vaccinology. Through transparent and balanced messaging, we can advocate for measles vaccination and substantially reduce the global measles burden.

Biography

Ozlem Equils is a former Associate Professor of Pediatric Infectious Diseases at the CSMC/UCLA School of Medicine and former co-chair of Adolescent Immunizations Subcommittee at the Immunization Coalition of Los Angeles County Dept of Public Health. She is a board-certified pediatrician with over 20 years of experience in drug development, spanning academia, biotech/pharma and public health. Her research has focused on host-microbial immune interactions, vaccinology, public health, health literacy and health policy. Dr Equils serves on the Executive Board of the American Academy of Pediatrics – California Chapter 2, and she is a member of the Institutional Biosafety Committee at Cedars-Sinai Medical Center. She is also the founder and president of a public health education and research nonprofit, MiOra.org, dedicated to improving health literacy and access (oequils@miora.org).

Funding Statement

The work was supported by the MiOra.

Disclosure statement

No potential conflict of interest was reported by the author(s).