Risk Index for Measles outbreak in Bulgaria for the period 2001 – 2024

Background/Objectives: Measles is a highly contagious, vaccine-preventable infectious disease. According to the ECDC report “Measles on the rise in the EU/EEA: considerations for public health response” [1], urgent action is required to address the increasing spread of measles and insufficient vaccination coverage across the EU. This study aims to develop a mathematical model for assessing the risk of measles outbreak/s and virus transmission in Bulgaria from 2001 to 2024. To achieve this, a Risk Index (RI) for measles outbreak was calculated based on age-structured immunization coverage and demographic trends.

Methods: Data on immunization coverage and demographic dynamics in Bulgaria were collected from 1971 onward,, encompassing a 50-year period. Census records dating back to 1970 were used to obtain age-structured demographic data. Established mathematical interpolation and extrapolation techniques were applied to estimate annual immunization coverage and demographic parameters. The Risk Index was calculated as a ratio of susceptible individuals to the total population.

Results: The Risk Index for measles outbreaks in Bulgaria was computed over a 50-year period. The key finding of this study is the definition and calculation of the Risk index, which reveals a concerning increase after 2015, with particularly alarming values projected for 2023 and beyond.

Conclusions: The high incidence of measles and its frequent complications pose a significant burden on healthcare systems, increasing hospitalizations and complicating prevention efforts, particularly among vulnerable populations. The proposed model provides valuable insight for health authorities to predict, prevent and localize outbreaks ensuring adequate healthcare preparedness, including sufficient medical resources and technical capacity. Additionally, the model can be adapted to assess the risk of outbreaks for other vaccine-preventable infectious diseases, such as influenza, pertussis and varicella, making it a useful tool for epidemic forecasting and prevention.

Measles is a highly contagious, vaccine-preventable infectious disease caused by the Measles Virus (MeV) [2]. Transmission occurs via respiratory route, with an incubation period of 10-14 days. On days 3-4, a characteristic maculopapular rash appears coinciding with the activation of the adaptive immune response and the initiation of virus clearance. Recovery from measles typically confers lifelong immunity against reinfection [3].

The MeV enters the body through the respiratory tract and subsequently spreads to immune cells and mucosal surfaces of the gastrointestinal, respiratory, and genitourinary tracts – i.e. multiorgan involvement. In rare cases, it can invade the central nervous system, leading to severe complications [2]. A key feature of measles infection is its profound immunosuppressive effect. While the initial lymphopenia resolves, measles significantly annihilates immune memory, which predetermines increased susceptibility to other infections, so the most measles deaths are caused by other infections [4]. Additionally, MeV can establish persistent infection, and in some cases, neurological disease may result from the chronic infection of neurons and glial cells [5].

Given its high transmissibility and potential for severe complications, measles poses a substantial public health risk, particularly for unvaccinated individuals, immunocompromised patients and malnourished children. According to ECDC, measles cases in EU/EEA are expected to rise due to suboptimal vaccination coverage in several member states, an increased risk of MeV importation from areas with high virus circulation and seasonal factors favoring transmission [1].

Before the introduction of widespread vaccination in 1963, large measles epidemics occurred approximately every 2 to 3 years, resulting in an estimated 2.6 million deaths annually. Routine mass vaccination of children remains the most effective health strategy for reducing measles-related mortality worldwide [6].

Measles is among the most contagious human disease, with a transmission index of approximately 0.99[7]. Its basic reproductive number, R0, which represents the number of individuals infected by a single case in a fully susceptible population, is estimated to range between 12 and 18 people [7].

Fortunately, measles can be effectively prevented through vaccination. High coverage with Measles Containing Vaccines (MCV) is critical for disease control. A second dose vaccination rate exceeding 95 is associated with approximately 96% efficacy in preventing measles, whereas a single-dose regimen provides less than 90% protection [8].

In Bulgaria, measles immunization was introduced in 1969 with a monovalent vaccine. The Measles-Mumps-Rubella (MMR) vaccine is now included in the national immunization schedule. However, vaccination coverage remains uneven, with certain regions exhibiting significantly lower rates. During the Covid-19 pandemic, stringent public health measures temporarily reduced the transmission of respiratory infections, incl. measles. However, the accumulation of a large susceptible population now raises concerns about the potential for future epidemic waves.

The objective of this study is to develop a mathematical model for assessing the risk of measles outbreak/s and virus transmission in Bulgaria between 2001 and 2024. The Risk Index (RI) for measles outbreak was calculated based on age-structured immunization coverage and demographic trends.

Data, sources and methods

Our mathematical model is based on previous studies on measles transmission in Bulgaria [9]. In particular, the measles vaccination policy in Bulgaria from 1969 to 2017 is illustrated in figure 1.

Figure 1: Measles-containing vaccine coverage in Bulgaria for the period 1969-2017, after [9].

Additional key data sources include:

• European Centre for Disease Prevention and Control (ECDC): Surveillance data by country [10], including vaccination coverage statistics from 2012 to 2017, as reported in The National Programme for Elimination of Measles and Rubella [11].
• National Center for Infectious and Parasitic Diseases (NCIPD): Data on immunizations from 2018 to 2023 [12]. 
• World Health Organization (WHO): Primary source for MMR immunization coverage (first and second doses), with data presented in table 1 [13]. 

The relationship between the epidemic process and vaccination during the period 1964-2004 is represented on table 2 [11], where the full set of the raw data is not included but only their min, max and average values:

The measles and rubella elimination country profile for Bulgaria is published online by the World Health Organization (WHO) [14]. The European Centre for Disease Prevention and Control (ECDC) provides vaccine schedules by country [10], including the historical changes in measles, rubella, and mumps vaccination policies in Bulgaria, summarized as follows:

Historical changes in the measles vaccination policy:

• 1969: Introduction of the measles vaccine in Bulgaria. 
• 1969–1971: Catch-up campaigns targeting all children aged 1-8 years without a history of measles infection. 
• 1972: Universal measles immunization implemented.
• 1972–1982: Routine immunization with a single dose of measles vaccine administered at 10 months of age or slightly older.
• 1976 & 1981: Follow-up immunization campaigns targeting children aged 2–14 years (1976) and 2–6 years (1981), regardless of vaccination status (re-immunization). 
• 1983: Universal immunization updated to include two doses of the measles vaccine. 
• 1983–1985: Routine immunization schedule.
• First dose: 12 months of age.
• Second dose: 4 years of age. 
• 1986–1992: Routine immunization schedule adjusted. 
• First dose: 12 months of age. 
• Second dose: 24 months of age.
• 1992: Follow-up immunization campaign for children aged 12–14 years, regardless of vaccination status. 
• 1993: Introduction of the combined measles-mumps-rubella (MMR) vaccine into the national immunization schedule, with the first dose administered at 13 months of age. 
• 1993-2000: Routine immunization with two doses.
• First dose (MMR): 13 months of age. 
• Second dose (monovalent measles vaccine): 12 years of age. 
• 2000–2001: MMR vaccine introduced for the second dose at 12 years of age. 
• Since 2001: Routine immunization with two doses of the MMR vaccine.
• First dose: 13 months of age. 
• Second dose: 12 years of age.

Data and methods for mathematical modeling of the risk measure for measles outbreak (2001 – 2024)

The primary objective of this study is to introduce a Risk Index (RI) as a quantitative measure of the epidemic outbreak risk at any given time. The Risk Index is defined as the ratio of susceptible (vulnerable) individuals to the total population in a specific period. Data Sources: This study relies on two primary datasets:

Demographic data : Age-structured demographic information for Bulgaria obtained from the National Statistical Institute (NSI) (https://nsi.bg/en), based on census data from 1960 onward.

Spline interpolation and extrapolation techniques were applied to estimate age-structured demographics for each year [13,15].

Vaccination coverage data: Immunization records obtained from sources detailed earlier.

Spline smoothing techniques were used to interpolate missing data points [15].

Methodology for calculating the risk index: The following steps outline the methodology for computing the number of susceptible individuals for each year after 2001.

1. For illustration, we demonstrate the calculation for the year 2006:

• The total number of susceptible individuals (SUSC_2006) is determined as those lacking immunity. 

2. Assumptions for individuals born before 1992:

• Nearly 100% vaccination coverage is assumed. 
• Those with zero vaccinations have 0% immunity. 
• Those with one vaccination are assumed to have 5% residual susceptibility. 

3. Categorization of individuals born after 1992 into three groups:

• Infants (< 1 year old in 2006): Not yet eligible for vaccination. 
• Children (< 12 years old in 2006): Either 
• Unvaccinated (0% coverage), or 
• Partially vaccinated (1 dose, 87% coverage). 
• Individuals ≥ 12 years old in 2006: Either 
• Unvaccinated (0% coverage), 
• Partially vaccinated (1 dose, 87% coverage), or
• Fully vaccinated (2 doses, 95% coverage). 

4. Adjustments for natural immunity:

• Individuals who recovered from measles during past epidemics were subtracted from the susceptible population:
• 25,000 individuals from the 2009-2010 outbreak. 
• 1,300 individuals from the 2019 outbreak.
• Many individuals were re-immunized during the 2009–2011 epidemic [16-19].

5. Waning immunity considerations:

• Evidence suggests that immunity wanes 10-15 years after vaccination, particularly with the French-manufactured vaccine used in Bulgaria after 2000 [20,21].

Following the implementation of the algorithm outlined above, we obtained a graphical representation of the number of susceptible individuals in Bulgaria between 2000 and 2023 (Figure 2).

Figure 2: The number of susceptible persons for the period 2000 – 2023.

Based on this data, we calculated the epidemiological Risk Index (RI), which quantifies the risk of a measles outbreak. The Risk Index is defined as the ratio of susceptible individuals to the total population at a given time:

$\text{RiskIndex}\left(\text{t}\right)=\frac{\text{SusceptiblesPerYear}\left(\text{t}\right)}{\text{Population}\left(\text{t}\right)}$

The computed values of the Risk Index are visualized in figure 3.

Figure 3: Risk Index for measles outbreaks in Bulgaria (2001–2023).

Key observations from figure 3

Population Estimates and Risk Index Sensitivity

The officially reported Bulgarian population is 6.5 million, but this figure may be an overestimate due to significant emigration.

If the actual population is lower, the Risk Index would be proportionally higher than reported.

Trend analysis and recent outbreaks

A notable increase in the Risk Index was observed in 2017, reaching levels comparable to 2009, when a major measles outbreak occurred.

The minor outbreaks in 2018–2019 align with this trend.

The rapid containment of the most recent epidemic may be attributed to swift intervention by health authorities, who were already vigilant due to the previous 2009–2010 outbreak.

Measles remains a major cause of childhood morbidity and mortality worldwide, despite being a vaccine-preventable disease [1,22]. Measles is the ideal virus for eradication through vaccination: there is only one serotype, lacks an animal reservoir and presents clear clinical symptoms that allow for effective epidemiological surveillance using highly sensitive and specific diagnostic tests [2]. In response, the Global Vaccine Action Plan (GVAP) aimed to eliminate measles in at least five WHO regions by 2020 [24]. Similarly, the Immunization Agenda IA2030 has committed to eliminating measles in at least five of the six WHO regions by 2030 [23,24]. Despite these efforts, measles persists, particularly in Europe, where suboptimal vaccination coverage has led to outbreaks. In 2023 alone, 9010 measles cases, 4259 hospitalizations and 2 measles-related deaths were reported to the WHO’s Centralized Information System for Infectious Diseases (CISID) [25-27]. These figures highlight the urgent need for enhanced surveillance, improved vaccine uptake, and rapid outbreak response measures.

Bulgaria introduced measles immunization in 1969 using a monovalent vaccine, later transitioning to a two-dose MMR vaccination schedule in 1993 [10].While early vaccination campaigns significantly reduced measles incidence, immunization rates have fluctuated over the decades , leading to pockets of susceptible individuals across different age groups. During the Covid-19 pandemic, strict public health measures temporarily reduced the spread of many respiratory infections, incl. measles. However, these same restrictions led to declining vaccination rates both in Bulgaria and across Europe [13]. From 2019 to 2023 national measles vaccination coverage and herd immunity levels deteriorated, increasing the risk of future outbreaks. Multiple factors contribute to this decline, including: vaccine hesitancy and misinformation; reduced routine immunization during the pandemic, leading to missed doses; increased travel to regions with low vaccination rates, facilitating virus importation; migrant populations with lower immunization coverage, increasing susceptibility. Given these challenges, continuous measles risk assessment and preparedness are essential.

This study introduces Risk Index, as a predictive tool for epidemic monitoring. The RI for measles outbreak prediction is based on the ratio of susceptible individuals to the total population. The model’s accuracy was validated using historical epidemic data, particularly the 2018 outbreak, demonstrating its effectiveness in forecasting disease trends. The Risk Index can be used in two primary ways: 1. Real-time outbreak prediction, estimating measles spread in different epidemiological scenarios (i.g., with/without vaccination campaigns); 2. Strategic planning for public health authorities, allowing for timely interventions, such as targeted immunization campaigns and resource allocation for hospital preparedness. Additionally, this model is adaptable for other vaccine-preventable infectious diseases such as influenza, pertussis, and varicella, making it a valuable tool for broader epidemic monitoring and prevention efforts.

Challenges in measles control and future considerations. Despite widespread vaccination, measles outbreaks continue to occur, often affecting both unvaccinated and vaccinated individuals. Several important observations arise from Bulgaria’s 2009-2010 epidemic: A significant proportion of infected individuals had received one dose of the vaccine. Single-dose vaccination confers only ~87% protection, while two-dose vaccination reaches ~95% efficacy. Non-vaccinated individuals remain at 100% risk, experiencing symptomatic disease with no asymptomatic carriers. This underscores the importance of maintaining high two-dose coverage to ensure herd immunity and prevent epidemic cycles. Another critical concern is waning immunity over time. Studies suggest that measles immunity may decline 10-15 years post vaccination, particularly among those who received the French-manufactured vaccine used in Bulgaria after 2000 [20,21].

If this trend continues, previously vaccinated individuals may re-enter the susceptible population, creating an “epidemiological reservoir” of adults at risk for future outbreaks.

Public Health Implications and Recommendations to effectively prevent and control future measles outbreaks, the following public health strategies should be prioritized:

1. Strengthening routine vaccination programs to ensure >95% two-dose coverage nationwide. 
2. Enhancing surveillance systems by integrating real-time Risk Index monitoring into national public health decision-making. 
3. Targeting high-risk populations (e.g., vaccine-hesitant communities, migrant populations) through localized immunization campaigns.
4. Implementing catch-up vaccination programs to immunize older children, adolescents, and adults who missed routine doses.
5. Addressing vaccine hesitancy through evidence-based health communication strategies and public awareness campaigns.

This study highlights the growing measles risk in Bulgaria and emphasizes the urgent need for improved vaccination strategies. The proposed Risk Index model offers a quantitative approach to outbreak prediction and epidemic preparedness. Given the ongoing challenges of vaccine hesitancy, waning immunity, and increased global mobility, proactive public health interventions are essential to achieve sustainable measles elimination.

Measles remains a significant public health concern due to its high transmissibility and potential for severe complications, which can strain healthcare systems by increasing hospitalizations and complicating the protection of vulnerable populations. The proposed Risk Index (RI) model provides a valuable tool for health authorities, enabling them to: Anticipate and prepare for measles outbreaks under different epidemiological scenarios. Implement timely and effective containment measures, including public health interventions, vaccination campaigns, and hospital resource allocation. Enhance outbreak surveillance and response strategies, reducing the impact of measles epidemics. Additionally, the model’s adaptability extends beyond measles, making it applicable for predicting and preventing outbreaks of other contagious vaccine-preventable diseases, such as influenza, pertussis (whooping cough), and varicella (chickenpox). Finally, the Risk Index could serve as a complementary indicator to vaccine coverage rates and herd immunity thresholds, supporting WHO’s measles elimination verification efforts at both national and regional levels.

Conceptualization, R.A. and H.B.; methodology, O.K. and T.V.; software, G.S.; investigation, O.K. and G.B.; All authors have read and agreed to the published version of the manuscript.

This research was funded by Bulgarian NSF, grant number KP-06-N52-1.

We have included references to all data used. All data used are open.

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results

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