Characterization of Vaccine Breakthrough Cases during Measles Outbreaks in Milan and Surrounding Areas, Italy, 2017-2021

Abstract

Despite the existence of an effective live-attenuated vaccine, measles can appear in vaccinated individuals. We investigated breakthrough measles cases identified during our surveillance activities within the measles/rubella surveillance network (MoRoNet) in Milan and surrounding areas (Northern Italy). Between 2017 and 2021, we confirmed measles virus (genotypes B3 or D8) infections in 653 patients and 51 of these (7.8%) were vaccinees. Among vaccinated individuals whose serum was available, a secondary failure was evidenced in 69.4% (25/36) of cases while 11 patients (30.6%) were non-responders. Non-responders were more frequently hospitalized and had significantly lower Ct values in both respiratory and urine samples. Median age and time since the last immunization were similar in the two groups. Importantly, we identified onward transmissions from vaccine failure cases. Vaccinees were involved in 20 outbreaks, in 10 of them they were able to transmit the virus, and in 8 of them, they were the index case. Comparing viral hemagglutinin sequences from vaccinated and non-vaccinated subjects did not show a specific mutation pattern. These results suggest that vaccination failure was likely due to the poor immune response of single individuals and highlights the importance of identifying breakthrough cases and characterizing their clinical and virologic profiles.

Keywords: hemagglutinin; measles vaccine; measles virus; vaccination failure.

Figure 1

Measles cases in Milan and its surroundings (Northern Italy) during the years 2017–2021. (A) The proportion of measles cases identified during the study period. (B) The proportion of measles cases according to vaccination status and year of sample collection.

Figure 2

Patient inclusion flow-chart.

Figure 3

Phylogenetic analysis of genotype B3 H nucleotide sequences belonging to clade B3-400V. The tree was obtained with the maximum-likelihood method [32], based on the Kimura 2 parameters model [33], identified as the best-fitting model after the model test analysis, using MEGA 11 [28]. A discrete Gamma distribution was used to model the evolutionary rate differences among sites (+G = 0.1) and branch support (100 bootstrap iterations [29]) is provided next to nodes. The tree was built using full-length sequences and the phylogenetic placement of a few partial sequences was manually placed on the tree based on a separate phylogenetic analysis with partial H genes [23]. Strain MVi/Ibdan.NIE/9.98/8 was used as an outgroup. Sequences from Lombardy are indicated by an empty circle for non-vaccinated individuals or a square shape for vaccinees (green: primary vaccination failure, orange: secondary vaccination failure, and purple: uncharacterized vaccination failure). Amino acid mutations associated with branches, including studied strains, are indicated in white boxes on the left, while those identified in single strains are indicated on the right by white, green, or orange boxes for non-vaccinated, primary, and secondary vaccination failure, respectively.

Figure 4

Phylogenetic analysis of genotype D8 H nucleotide sequences belonging to clade D8-400T. The tree was obtained with the maximum-likelihood method [32], based on the Kimura 2 parameters model [33], identified as the best-fitting model after the model test analysis, using MEGA 11 [28]. A discrete Gamma distribution was used to model the evolutionary rate differences among sites (+G = 0.2054) and branch support (100 bootstrap iterations [29]) is provided next to nodes. The tree was built using only full-length sequences and the phylogenetic placement of a few partial sequences was manually placed on the tree based on a separate phylogenetic analysis with partial H genes [23]. Other D8 sequences (MVi/Alicante.SPA/19.03 and MVi/Washington.USA/12.99) were used as an outgroup. Sequences from Lombardy are indicated by an empty circle for non-vaccinated individuals or a square shape for vaccinees (green: primary vaccination failure, orange: secondary vaccination failure, and purple: uncharacterized vaccination failure). Amino acid mutations associated with branches including, studied strains, are indicated in white boxes on the left, while those identified in single strains are indicated on the right by white, green, or orange boxes for non-vaccinated, primary, and secondary vaccination failure, respectively.