Amid a rise in cases of antibiotic-resistant gonorrhoea, authors of a paper in Nature Communications present their research into the immune response gonorrhoea in the hope that it will enable the development of effective vaccines. They conducted a trial of 4CMenB in adults in coastal Kenya who have high exposure to Neisseria gonorrhoea (Ng), concluding that cross-protection provided by the vaccine against gonorrhoea could be explained by cross-reaction against a “diverse selection” of antigens derived from the outer membrane vesicles (OMV) component. The research was the result of a collaboration between scientists at the University of Manchester and Oxford and the KEMRI/Wellcome Trust Unity in Kenya.
Gonorrhoea vaccine challenges
Neisseria gonorrhoea (Ng) is the Gram-negative diplococcus that causes the sexually transmitted infection gonorrhoea. Approximately 82.4 million people were newly infected with Ng in 2020, which makes it the second most prevalent STI worldwide after Chlamydia trachomatis (CT). Gonorrhoea affects reproductive health and newborn well-being and is a “strong” co-factor in HIV transmission. Resistance to frontline antibiotics is “high and increasing”, so the development of an effective vaccine is an increasingly pressing need.
Vaccine development is complicated by the fact that infection with Ng does not usually induce protective immunity. Clinical trials of gonococcal vaccine candidates have “not been encouraging”. However, recent data suggest that an effective vaccine is “feasible”. A vaccine (MeNZB) derived from the related bacterium Neisseria meningitidis (Nm) had “most” efficacy but was linked to a reduction in gonorrhoea diagnoses. It is inferred that antigens within the Nm outer membrane vesicle (OMV) vaccine-elicited antibodies cross-reacted with gonococcal antigens.
4CMenB
GSK’s 4CMenB (Bexsero) combines an OMV preparation from the same Nm strain as MeNZB with five recombinant antigens; three of these are responsible for enhancing protection against Nm infection. The vaccine has demonstrated cross-protection against gonorrhoea and studies have identified a range of Ng OMV-derived proteins that “could play a protective role as target antigens” for antibodies induced through vaccination with 4CMenB.
The study
In the study the authors combine antigen microarrays with statistical and machine-learning methods to obtain a “comprehensive view” of how antigen reactivity profiles are linked to vaccination with 4CMenB and infection in a highly exposed human population. They selected a coastal Kenyan population that is at “high risk of infection”. 62 participants were screened to receive the vaccine 50 (37 men and 13 women) were enrolled and received their first vaccination. 47 participants (36 men and 11 women) received a second vaccination.
The researchers at University of Manchester identified the antibody response patterns and compared vaccine recipients with individuals infected with gonorrhoea. This has “important ramifications” for Ng vaccine design. For example, the “limited” protective effect of 4CMenB against gonorrhoea implies that cross-protection induced through meningococcal antigens, combined with OMV’s adjuvant properties, “could be responsible”. Of the four recombinant antigens examined, only NHBA is surface-exposed and “not likely to be solely responsible for protection”. Furthermore, the more durable responses to the OMV antigens indicate an environmental “adjuvant-like effect” that could lead to longer-lasting responses.
The authors note that antibody responses to certain antigens correlate, which suggests that a vaccine would not only demand the selection of component antigens and adjuvants, but a “consideration of how the whole formulation is able to induce long-lasting, protective immunity”. The University of Oxford’s Professor Chris Tang, project lead, describes the work as an “important step along the road to developing Ng vaccines”.
“We have a better idea of which responses are generated by partially protective vaccination compared with infection.”
Professor Jeremy Derrick from the University of Manchester identifies “wide implications” for “revisiting vaccine design for other bacterial pathogens using these new methods”. This is particularly important for those where antimicrobial resistance is a “problem”.
“We hope that the application of these technologies will enable progress towards vaccines against other pathogens.”
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