Profiling IgG and IgA antibody responses during vaccination and infection in a high-risk gonorrhoea population

Abstract

Development of a vaccine against gonorrhoea is a global priority, driven by the rise in antibiotic resistance. Although Neisseria gonorrhoeae (Ng) infection does not induce substantial protective immunity, highly exposed individuals may develop immunity against re-infection with the same strain. Retrospective epidemiological studies have shown that vaccines containing Neisseria meningitidis (Nm) outer membrane vesicles (OMVs) provide a degree of cross-protection against Ng infection. We conducted a clinical trial (NCT04297436) of 4CMenB (Bexsero, GSK), a licensed Nm vaccine containing OMVs and recombinant antigens, comprising a single arm, open label study of two doses with 50 adults in coastal Kenya who have high exposure to Ng. Data from a Ng antigen microarray established that serum IgG and IgA reactivities against the gonococcal homologs of the recombinant antigens in the vaccine peaked at 10 but had declined by 24 weeks. For most reactive OMV-derived antigens, the reverse was the case. A cohort of similar individuals with laboratory-confirmed gonococcal infection were compared before, during, and after infection: their reactivities were weaker and differed from the vaccinated cohort. We conclude that the cross-protection of the 4CMenB vaccine against gonorrhoea could be explained by cross-reaction against a diverse selection of antigens derived from the OMV component.

Fig. 1. ASCA separation of IgG antibody profiles by vaccine recipient.

In the left-hand panels, each point represents a profile derived from IgG reactivity against antigens across the array. Comp 1 and Comp 2 represent the first and second principal components in the ASCA analysis. Confidence ellipsoids are plotted that reflect the estimated variation of the effect level means at 40, 68 and 95%. Open symbols represent individual serum samples; ellipsoid centres are plotted as filled symbols. Righthand panels show the antigens with the highest loadings for each component. A ASCA calculation with all antigens included. B As A but with NHBA, Factor H binding protein (fHbp), GNA2091 and GNA1030 removed.

Fig. 2. ASCA separation of IgA antibody profiles by vaccine recipient.

In the left-hand panels, each point represents a profile derived from IgA reactivity against antigens across the array. Comp 1 and Comp 2 represent the first and second principal components in the ASCA analysis. Confidence ellipsoids are plotted that reflect the estimated variation of the effect level means at 40, 68 and 95%. Open symbols represent individual serum samples; ellipsoid centres are plotted as filled symbols. Righthand panels show the antigens with the highest loadings for each component. A ASCA calculation with all antigens included. B As (A) but without the recombinant antigens, NHBA, fHbp, GNA2091 and GNA1030.

Fig. 3. tSNE separation of antibody profiles by antigen.

Each point represents an antigen profile derived from vaccinated individuals. A Comparison of IgG and IgA responses for stimulation of antibody reactivity against antigens between t0/t10 (left) and t0/t24 (right). IgG reactivities are coloured in red and IgA in green. B Separation of IgG and IgA reactivities against array antigens for the t10-t0 dataset. The PorB variants are coloured in blue, the Opa variants in orange, the four 4CMenB recombinant antigens in red and all others in black. C as for (B), but for the t24-t0 dataset.

Fig. 4. Violin plots for IgG and IgA responses against the gonococcal variants of the recombinant protein components in 4CMenB.

A IgG responses. B IgA responses. Box plots are superimposed on each violin plot, providing the median, two hinges which correspond to the first and third quartiles and ‘whiskers’ which extend to the ‘outlier’ points, which are plotted explicitly. In both (A, B), n = 47, for t0, t10 and t24.

Fig. 5. Violin plots for IgG responses in 4CMenB-vaccinated subjects against selected gonococcal antigens.

Antigen details are given in Table 1. Box plots are superimposed on each violin plot, providing the median, two hinges which correspond to the first and third quartiles and ‘whiskers’ which extend to the ‘outlier’ points, which are plotted explicitly. n = 47, for t0, t10 and t24.

Fig. 6. Violin plots for IgA responses in 4CMenB-vaccinated subjects against selected gonococcal antigens.

Antigen details are given in Table 2. Box plots are superimposed on each violin plot, providing the median, two hinges which correspond to the first and third quartiles and ‘whiskers’ which extend to the ‘outlier’ points, which are plotted explicitly. n = 47, for t0, t10 and t24.

Fig. 7. ASCA separation of antibody profiles in non-vaccinated individuals with a Ng infection.

Layout and details are as for Figs. 1, 2, with a central magnified panel inserted. Comp 1 and Comp 2 represent the first and second principal components in the ASCA analysis. Confidence ellipsoids are plotted that reflect the estimated variation of the effect level means at 40, 68 and 95%. Open symbols represent individual serum samples; ellipsoid centres are plotted as filled symbols. Righthand panels show the antigens with the highest loadings for each component.

Fig. 8. Comparison of IgG and IgA antigen reactivity profiles in vaccinated individuals and individuals from the historical cohort.

The vaccine and infection cohort datasets were merged, antigens from the four recombinant antigens were removed and either IgG or IgA reactivities were separated by ASCA analysis, as in Figs. 1, 2, 7. Factors used were Ng infection or vaccine recipient identity and Before/During/After/t10/t24. The t0 dataset from the vaccinated cohort was merged with the ‘Before’ dataset in the Ng infection cohort. Layout and details are as for these previous figures, with a central magnified panel inserted. Comp 1 and Comp 2 represent the first and second principal components in the ASCA analysis. Confidence ellipsoids are plotted that reflect the estimated variation of the effect level means at 40, 68 and 95%. Open symbols represent individual serum samples; ellipsoid centres are plotted as filled symbols. Arrows in the magnified IgG panel indicate transitions between before to t10 and t10 to t24.