Quantification of Waning Immunity After Measles Vaccination—Evidence From a Seroprevalence Study
Slovakia is one of the few countries where vaccination against measles is mandatory. Thanks to this strategy, Slovakia has been achieving a high level of measles vaccination coverage for a long time. As the regular administrative vaccination supervision shows, measles, mumps, and rubella (MMR) vaccination coverage at the national level has been above 98% for the first dose for birth cohorts 1992–2010 and for the second dose for birth cohorts 1984–2002. Since the year 2010, a noticeable decrease in vaccination coverage at the national level has been observed, with stabilization at a value just above 95% in recent years (1, 2).
At the regional level, vaccination coverage has been above 95% for the first dose of MMR vaccine up to birth cohort 2008 and for the second dose up to birth cohort 2000 in almost all 79 districts of Slovakia. As overall vaccination coverage decreases, the proportion of districts in which the required vaccination coverage has not been achieved increases. In recent years, the proportion of districts with vaccination coverage below 95% was close to 50%; in several districts and some birth cohorts, vaccination coverage was even below 90%. In general, the districts with the lowest vaccination coverage are concentrated around Bratislava and in eastern Slovakia. Low vaccination coverage around Bratislava is most likely linked to a strong antivaccination campaign. In the districts of eastern Slovakia, it is probably associated with the presence of numerous Roma, an ethnic minority group (1–4).
After introduction of the measles vaccine and its inclusion in the vaccination program in 1969, the incidence of measles in Slovakia gradually decreased. The last outbreak at the national level occurred in 1984. During the seasons 1992/1993, 1997/1998, and 2018/2019, outbreaks with several hundred cases of measles were recorded in marginalized Roma communities (1, 4).
There is strong evidence that immunity is stronger after overcoming measles than after vaccination (5). Several studies have shown that postvaccination antibody levels decline over time (6–9), but to our knowledge the role of waning immunity in achieving and sustaining herd immunity has not yet been clarified. Our aim in this study was to quantify waning immunity following the first and second doses of MMR vaccine from seroprevalence data. Naturally, a longitudinal study would be more suitable for analysis of waning immunity. In 2018, however, a population-based seroprevalence study was carried out in Slovakia, so we were able to use national survey data for this task (10). The robustness of this study allowed us to quantify a decline in antibody levels over increasing time since the last vaccination.
METHODS
This study followed from the Immunological Survey, a cross-sectional serosurvey study carried out in the Slovak Republic in 2018 (IS 2018) and coordinated by the Slovak Public Health Authority (10). The design and sampling method of IS 2018 have been described in detail previously (10). In brief, serum sample collection for IS 2018 was conducted by pediatricians and general practitioners from June to September 2018. A total of 4,218 serum samples were collected. The sampling, specimen collection, and serological analysis were harmonized with the immunological methodological survey carried out in the Slovak Republic in 2002 (11).
We studied waning immunity separately after the first dose of MMR vaccine and after the second dose of the vaccine. Participants were selected for this purpose from IS 2018 using several inclusion and exclusion criteria (see Web Figure 1, available at https://doi.org/10.1093/aje/kwad065). Exclusion and inclusion criteria were chosen to reflect the currently valid vaccination schedule in Slovakia, with some tolerance in the timing of individual vaccination. At the time of the study, the first dose of MMR vaccine was normally given at 15–18 months of age and the second dose was given at 11 years of age. In the past, for cohorts born after 1984, vaccination schedules were approximately similar (10). Among all IS 2018 participants, 1,337 individuals vaccinated with the first dose and 1,104 individuals vaccinated with both doses met our criteria.
Ethical approval
The study was approved by the Ethical Committee of the Ministry of Health of the Slovak Republic, the Ethical Committee of the Trenčín self-governing region, and the Ethical Committee of the Bratislava self-governing region. Informed consent was obtained from all participants or their parents before the study.
Laboratory assay
Serological tests were performed in the National Reference Centre for Measles, Mumps and Rubella of the Public Health Authority of the Slovak Republic. Serum samples were tested for the presence of immunoglobulin G (IgG) antibodies by enzyme immunoassay using a commercial kit (Enzygnost Anti-Measles Virus/IgG; Siemens, Marburg, Germany) according to the manufacturer’s instructions. Levels of antibodies were measured as a continuous variable and then were categorized: Persons with an antibody level greater than 350 mUI/mL were considered seropositive, persons with a level less than 150 mUI/mL were deemed seronegative, and those with levels between 150 mUI/mL and 350 mUI/mL were categorized as borderline-seropositive (low positive).
Estimation of waning immunity
There are 2 major factors responsible for MMR vaccine failure. Primary vaccination failure (PVF) is defined as a failure of the host/vaccinee to mount a protective immune response after vaccination (12). Secondary vaccination failure (SVF) or waning immunity is accompanied by a decrease in antibody levels over time under the protective threshold among individuals who have previously generated antibodies against measles. In order to quantify the waning immunity, it is important to distinguish between these 2 types of vaccine failure.
where w denotes the waning (decay) rate (13).
Measles-vaccine–induced antibody titers follow a normal distribution after natural logarithmic transformation. Under this assumption, the following 4 parameters are considered essential for estimating seroprevalence at different time points after vaccination: the initial GMT(0) postvaccination; the standard deviation (SD) of the distribution of antibody titers (SD = 1); the waning rate of antibody titers (w); and the cutoff of seropositivity (Cneg = 150 mUI/mL).
In addition, equation 2 enables us to determine the proportion of persons who had a borderline level of antibodies—that is, lower than Cborder = 350 mUI/ml but higher than Cneg = 150 mUI/mL—as a difference: P(x < ln(Cborder)) − P(x < ln(Cneg)).
Note that not all seronegative individuals can directly be considered as being susceptible to infection due to SVF. In vaccinees whose IgG antibody levels have fallen below the protective limit, their cellular immunity still may work (12).
Statistical analysis
Our main objective in this study was to assess the possible dependence of antibody levels on the amount of time since the last vaccination. The linear regression method was used to quantify this relationship. We considered the logarithm of antibody levels a dependent variable and the age of the participant an independent variable. Analysis was stratified by sex and county. The variable age was measured on a continuous scale in years. Considering age instead of time since last vaccination allowed for monitoring of waning immunity on the population level. Under the assumption of a fixed vaccination schedule, there is a one-to-one correspondence between the age of individuals and time since the last vaccination, so these 2 variables are strongly correlated and may be interchanged.
For first-dose MMR vaccinees, participants with seronegative values were considered to have PVF, and therefore they were not included in the regression model (14). On the other hand, participants who were found to be seronegative after 2 doses of vaccine were considered to have SVF. Since the latter data were left-censored when the values fell below the assay’s lowest measurable concentration (the limit of quantification), the Tobit model of linear regression was applied in this case. Data analysis and modeling was performed using Microsoft Excel (Microsoft Corporation, Redmond, Washington) and the “censReg” package in R software (R Foundation for Statistical Computing, Vienna, Austria) (15, 16).
Based on the estimated regression equation, we predicted the value for SVF and the proportion of low seropositive (borderline) individuals for each respective age cohort. Finally, we compared the predicted proportions of seronegative and low positive groups in the respective age cohorts with those observed in IS 2018.
RESULTS
Waning immunity after the first dose
Among persons vaccinated with a first dose of MMR vaccine, approximately 2.4% (95% confidence interval (CI): 1.6, 3.4) did not have detectable levels of antibodies. They were not included in the regression analysis. This value was considered to indicate PVF.
Our findings based on the fitted regression model can be summarized as follows. The intercept after exponential transformation was equal to 3,047 mUI/mL (95% CI: 2,727, 3,404), and the rate of waning immunity was estimated to be w = 9.7% (95% CI: 7.7, 11.6) per year. The initial geometric mean antibody level (GMT(0)) postvaccination (age = 1.5 years) was 2,634 mUI/mL (F(1, 1,303); P < 0.001) (Figure 1A). Results of the analysis stratified by sex and county are shown in Web Table 1.
Waning immunity after the first dose of measles, mumps, and rubella vaccine in the Slovak Republic, 2018. A) Measles immunoglobulin G antibody levels (log scale) according to the age of participants. A linear regression line with appropriate percentile lines is shown. B) Proportions of seronegative and borderline (low seropositive) individuals in certain age cohorts, data from Immunological Survey 2018 (IS 2018), and prediction. Error bars represent exact 95% confidence intervals for the proportions of seronegative and borderline (low seropositive) individuals.
According to equations 1 and 2, our estimates showed that the proportion of participants with antibody levels below the detectable limit due to SVF was low during the study period. As seen in Figure 1B, the estimated proportion of seronegative individuals increased with increasing age and reached almost 2.5% at the end of the 10-year period between the first and second doses.
A similar observation can be made for the borderline levels of antibodies. This proportion also increased with age (time since last vaccination) and roughly followed the patterns observed for individuals with borderline levels of antibodies in age cohorts from IS 2018. At the end of the 10-year period between the first and second doses, they exceeded 10%.
Waning immunity after the second dose
The overall proportion of seronegative individuals in the group receiving 2 doses of MMR vaccine was 5.5% (95% CI: 4.2, 7.0). PVF was assumed to be 0.
The intercept after exponential transformation was 2,144 mUI/mL (95% CI: 1,692, 2,717). The rate of waning of immunity after the second dose was estimated to be significantly lower than that after the first dose: w = 4.8% (95% CI: 3.5, 6.1) per year (Wald statistic = 52.22, P < 0.001). The geometric mean antibody level after the second shot (age = 10 years) was 1,331 mUI/mL (Figure 2A). Results of the analysis stratified by sex and county are shown in Web Table 2.
Waning immunity after the second dose of measles, mumps, and rubella vaccine in the Slovak Republic, 2018. A) Measles immunoglobulin G antibody levels (log scale) according to the age of participants. A linear regression line with appropriate percentile lines is shown. B) Proportions of seronegative and borderline (low seropositive) individuals in certain age cohorts, data from Immunological Survey 2018 (IS 2018), and prediction. Error bars represent exact 95% confidence intervals for the proportion of seronegative/borderline individuals.
After substituting the estimated regression coefficients in equations 1 and 2, we predicted that approximately 2% of the just-vaccinated age cohort had antibodies below the limit of detection. However, the proportion of seronegative individuals, as well as the proportion of borderline individuals, was constantly increasing with increasing age (time since last vaccination). By the end of the predictive period (which corresponded to the age of 33 years, i.e., cohorts born in 1985–1990), up to 10%–15% seronegatives and 20%–25% low positives could be expected (Figure 2B).
DISCUSSION
Surprisingly, the average proportion of seronegative individuals in this study was higher in the fully vaccinated group than in the group vaccinated with only 1 dose of MMR. The first dose of MMR vaccine initially induces a high antibody response. Therefore, the reason why a certain proportion of individuals are seronegative in the first years after initial vaccination lies mainly in PVF (14). The PVF value of 2.4% in this study was below the expected value of 4%–5% (12, 17).
However, the average level of antibodies decreased with age (increasing time since administration of the first dose), and thus the proportion of seronegative individuals could potentially increase; it did not reach a substantial level at the time of the second dose, which is similar to other studies (7, 8). The second dose can be considered a dose of confidence (12). In contrast, the proportion of seronegative individuals had not significantly changed after administration of the second dose and was increasing with age. This can be explained by the fact that PVF in our study was very low and SVF begins to have a comparable impact on seronegativity just at the age of the second dose (10 years of age).
Our findings also coincide with the results of other studies (8, 12): The second dose of MMR vaccine cannot be considered a universal booster. The average increase in antibody levels after the second shot was not significant, but the rate of waning immunity after the second dose was lower than after the first dose. This may indicate an influence of the second dose as a booster only in some subpopulations of vaccinees or a slowing down of the waning rate. However, these conclusions would best be validated through a longitudinal study.
In comparison with the longitudinal study of Seagle et al. (18), which investigated the waning rate in relation to the magnitude of the immune response after the second dose, our estimate of the waning rate was lower. Seagle et al. stated that among persons with the same baseline titer and no response to the second dose of MMR vaccine (MMR2), levels of measles antibodies declined an average of 9.7% per year (18). Persons with some MMR2 response experienced a slower decline (2- to 4-fold increased response: 6.3% per year; more than 4-fold increased response: 7.4% per year) (18). Each of these waning rates was above that estimated in our study (4.8%).
The meta-analysis by Schenk et al. (17) provided estimates of PVF (seroconversion rate) and SVF (waning rate) for measles. The method of estimating the waning rate was different from that used in this study—the waning rate was defined as the proportion of seropositive individuals at time point t + 1, which is a factor e−waning rate from the proportion of seropositives at time point t (17). Even though the definition was different, the authors conducted simple hypothetical projection based on the overall meta-analysis results to display how the proportion of seroconverted individuals would evolve over a time span of 50 years, which can be compared with our prediction. Our prediction is somewhat less pessimistic and leads to a lower proportion of seronegatives according to time since last vaccination.
Currently, the epidemiologic situation in Slovakia in relation to measles is favorable. The last epidemic outbreaks occurred in season 2018/2019 and resulted in almost 900 cases. The epidemics occurred in eastern Slovakia, in areas where a high proportion of the Roma minority live.
The first measles outbreak had an explosive character and affected the districts of Michalovce and Sobrance, despite the relatively high declared vaccination coverage (4). During the summer of 2018, approximately 450 cases were registered. Up to 96% of these cases were among persons living in housing conditions with missing or substandard hygienic amenities (1). According to the individual medical records, up to 30% of case patients had been vaccinated with 2 doses of the measles vaccine and another 30% with 1 dose (19). However, because further examination revealed that of 90 cases with a medical record of vaccination with 2 doses of MMR, only 9 persons had positive IgG antibodies against rubella, the remaining 81 had negative antibodies (4). Given that MMR vaccines are highly immunogenic (18, 20), there are serious doubts about the reliability of medical records within the affected population. For this reason, it was not possible to quantitatively evaluate the role of waning immunity in this epidemic.
The second measles outbreak continued protractedly in the district of Trebišov, which belongs to districts with a relatively lower or average declared level of vaccination coverage. Sporadic cases and several smaller outbreaks occurred in other districts, but there was no explosive increase in the number of cases. Approximately 70% of the cases in the second outbreak were among unvaccinated persons, especially children under 10 years of age. Occasionally, the disease was also transmitted to persons who had received 2 doses (7% of cases) or 1 dose (20% of cases) of MMR vaccine (19).
In the light of the above-mentioned information on the last measles outbreaks in Slovakia, the key factor determining the speed and massiveness of measles spread in Slovakia remains the presence of unvaccinated individuals.
Surrounding countries—for instance, the Czech Republic—have reported several measles outbreaks in the last several years. In contrast to Slovakia, in the Czech Republic measles has spread mainly among young adults. In the Czech Republic, more than 70% of cases were in the age group ≥20 years, while in Slovakia this figure was only 21% (19, 21). Actually, waning immunity can be considered the underlying reason for the observed age difference in the affected groups. In the Czech Republic, the second dose is given 6–10 months after the first dose, that is, at the age of approximately 3 years. This is significantly earlier than in Slovakia (11th year of life), which results in a longer amount of time since the last vaccination among young adults in the Czech Republic than in Slovakia. Thus, the relatively large outbreaks among young adults in the Czech Republic might have been caused by SVF. This assumption can be supported by several serosurveys performed in the Czech Republic (22–25). These studies indicated a significant decline in immunity in older vaccinated cohorts.
Limitations
The main limitation of this seroprevalence study lies in its cross-sectional design. Estimation of the waning rate would be principally more accurate if data were collected in a longitudinal survey. However, longitudinal studies are expensive and time-consuming in comparison with cross-sectional studies, since the results take a long time to come in. Such studies are logistically demanding and require a large commitment from all of the parties involved.
Further, there were several other limitations related to data collected in the seroprevalence study. First of all, the sample size was not the same in all age cohorts: The study focused mainly on children. Another limitation was the lack of information on the socioeconomic status of selected study participants, since those data were not collected at all. Therefore, it was not possible to account for potential confounding caused by socioeconomic determinants.
The statistical analysis itself can also be seen as a limitation to some extent. For estimation of the waning rate, only a linear regression model was used in this study. In fact, the decrease in the logarithm of the antibody level could show a more complicated structure. Further, we assumed that measles-vaccine–induced antibody titers follow a normal distribution after natural log transformation. However, not all data from the seroprevalence study support this assumption.
Finally, it should be noted that seronegativity in IgG antibodies does not necessarily mean susceptibility. Further investigation of the correlation between antibody levels and susceptibility to measles is needed.
Conclusion
Waning immunity, together with heterogeneity in vaccination coverage, can substantially increase the risk of measles outbreaks. Due to the currently favorable epidemiologic situation and high average vaccination coverage, the proportion of cohorts that do not come into contact with natural measles will most likely continue to increase in the future (26, 27). Thus, from a long-term perspective, waning immunity may have a significant impact on the population’s susceptibility to measles, and it is important to explore this phenomenon (28).
ACKNOWLEDGMENTS
Author affiliations: Department of Public Health, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic (Jana Zibolenová, Henrieta Hudečková, Eva Malobická, Martin Novák); Department of Applied Mathematics and Statistics, Faculty of Mathematics, Physics and Informatics, Comenius University in Bratislava, Bratislava, Slovak Republic (Zuzana Chladná); Department of Nuclear Physics and Biophysics, Faculty of Mathematics, Physics and Informatics, Comenius University in Bratislava, Bratislava, Slovak Republic (Iveta Waczulíková); and Public Health Authority of the Slovak Republic, Bratislava, Slovak Republic (Ján Mikas, Adriana Mečochová).
This work was supported by the Slovak Ministry of Health and the Public Health Authority of the Slovak Republic. The work of Z.C. was partly supported by the Slovak Scientific Grant Agency (Vedecká Grantová Agentúra (VEGA) grant 1/0755/22).
Data are available from Public Health Authority of the Slovak Republic upon reasonable request.
We thank all those who actively participated in the successful implementation of IS 2018, particularly the employees of the epidemiology departments of the regional public health authorities, the Department of Medical Microbiology of the Public Health Authority of the Slovak Republic, and the Department of Medical Microbiology of the Regional Public Health Office in Banská Bystrica. We extend special thanks to all 204 pediatricians and 228 general practitioners who collected the serum samples.
Portions of this work were presented at the 12th Slovak Vaccinology Congress, Tatranská Lomnica, Slovak Republic, September 23–25, 2021.
The views expressed in this article are those of the authors alone.
Conflict of interest: none declared.
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