Evaluation of the effect of maternally derived antibody on response to MMR vaccine in Thai infants

Abstract

Background: Although the number of measles cases declined globally in response to anti-measles immunisation campaigns, measles has re-emerged. A review of current vaccination policies is required to improve measles elimination strategies.

Methods: A pseudotype-based virus neutralisation assay (PVNA) was used to measure neutralising antibody titres in serum samples collected from Thai infants at six timepoints before and after two-doses of MMR (1&2) vaccination (ClinicalTrials.gov no. NCT02408926). Vesicular stomatitis virus (VSV) luciferase pseudotypes bearing the haemaglutinin (H) and fusion (F) glycoproteins of measles virus (MeV) were prepared. Serial dilutions of serum samples were incubated with VSV (MeV) pseudotypes and plated onto HEK293-human SLAM1 cells; the neutralising antibody titre was defined as the dilution resulting in 90% reduction in luciferase activity.

Results: Neutralising antibody titres in infants born with high levels of maternal immunity (H group) persisted at the time of the first MMR vaccination, and those infants did not respond effectively by developing protective titres. In contrast, infants with lower maternal immunity (L group) developed protective titres of antibody following vaccination. Responses to the second MMR vaccination were significantly higher (P = 0.0171, Wilcoxon signed-rank test) in the H group. The observed correlation between anti-MeV IgG level and neutralising antibody titre in Thai infants indicates the possibility of using rapid IgG testing as a surrogate measure for neutralising activity to define clinical protection levels within populations.

Conclusion: These results demonstrate that varying the timing of the first MMR immunisation according to the level of acquired maternal immunity could increase vaccination immunogenicity and hence accelerate measles eradication.

Keywords: Childhood vaccination; Maternal immunity; Measles-mumps-rubella (MMR); Neutralising antibody; Pseudotype-based virus neutralisation assay.

Fig. 1

The distribution of neutralising antibody titres in Thai infants against the Edmonston strain at 6 timepoints. Median titres with interquartile ranges are shown. The dotted blue line indicates the neutralising antibody titre of the WHO 3rd international standard (NIBSC 97/648) diluted to 120 mIU/mL, which is defined as the clinical protective concentration. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Neutralising antibody titres of samples collected from Thai infants from birth to 36 months. The dotted red line indicates the titre of the WHO 3rd international standard (NIBSC 97/648) diluted to 120 mIU/mL, which is defined as the clinical protective concentration. Closed triangles represent 38 of 48 infants who had undetectable neutralising antibody titres at Mo7. The remaining 10 infants with measurable titres at Mo7 are shown as open squares. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Comparing neutralising antibody titres between infants with high versus low maternal immunity levels. Median titres with interquartile ranges are shown. The dotted blue line indicates the neutralising antibody titre of the WHO 3rd international standard (NIBSC 97/648) diluted to 120 mIU/mL, which is defined as the clinical protective concentration. Asterisks indicate statistical significance (**** P values less than 0.0001; *** P values less than 0.001; * P values less than 0.05). Neutralising antibody titres of infants with high maternal immunity (H) were compared to the titres of infants in low maternal immunity group (L) at each timepoint (Mann-Whitney test). Neutralising antibody titres of samples collected after each dose of MMR vaccination were compared between the H and L groups (Wilcoxon matched-pairs signed-rank test). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Cross-neutralising antibodies against circulating measles strains B3 and D8 compared to Edmonston vaccine strain. Median titres with interquartile ranges are shown and the Wilcoxon signed-rank test was used for statistical analysis. Asterisks indicate statistical significance (*** P values less than 0.001; ** P values less than 0.01; * P values less than 0.05). Neutralising antibody titres against B3 were significantly higher than the titres against Edmonston at all four timepoints tested. Titres against D8 were significantly higher than the titres against Edmonston at birth and were significantly lower at 18 months.

Fig. 5

Correlation between measles specific IgG levels and neutralising antibody titres in Thai infants. The correlation between measles specific IgG and neutralising antibody titres were calculated (Rs = 0.47 at Cord, 0.79 at Mo2, 0.25 at Mo7, 0.76 at Mo18, 0.74 at Mo24 and 0.68 at Mo36; P value < 0.0001 at Cord, Mo2, Mo18, Mo24 and Mo36, P = 0.0571 at Mo7; Spearman’s rank correlation coefficient). The red lines indicate the titre of the 3rd WHO reference serum at 120 mIU/mL, defined as the protective titre. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)