JCVI advice on the use of meningococcal B vaccination for the prevention of gonorrhoea

Question 1

Background

Accepted Answer

The Joint Committee on Vaccination and Immunisation (JCVI) is an expert scientific advisory committee which advises the UK government on vaccination and immunisation matters.

Gonorrhoea epidemiology

Gonorrhoea is a bacterial sexually transmitted infection (STI) caused by the Neisseria gonorrhoeae bacterium. It is the second most commonly diagnosed STI in England, with around 80,000 diagnoses a year.

Gonorrhoea is transmitted through condomless vaginal, oral or anal sex, or genital contact with an infected partner. Even if an infected person has no symptoms the infection can still be transmitted. Typical symptoms of infection may include thick green or yellow discharge from the vagina or penis and pain on urination. Infection may also result in the following complications:

pelvic inflammatory disease
ectopic pregnancy and infertility in women and other people who have a womb or ovaries
painful infection in the testicles and prostate in men and other people who have testicles or a prostate

Gonorrhoea causes significant morbidity and remains a public health concern globally. Increased resistance to most antibiotics used to treat gonococcal infection has been reported worldwide, with extensively resistant strains exhibiting resistance to multiple antibiotic classes. The World Health Organization considers Neisseria gonorrhoeae to be a high priority pathogen due to this widespread antimicrobial resistance.

In the UK, the currently recommended first-line therapy is ceftriaxone, which belongs to a class of antibiotics called cephalosporins. While resistance to ceftriaxone remains very low in England, there has been an increase in ceftriaxone resistant cases in 2022. These were associated with travel to or from the Asia-Pacific region where ceftriaxone resistance is more commonly reported.

Gonorrhoea surveillance commenced in the UK over 100 years ago. Official statistics for STIs in 2022 from the UK Health Security Agency (UKHSA) highlights a rapid rise in gonorrhoea diagnosis in England. This follows an increasing trend in gonorrhoea since the early 2000s, with a large increase in diagnoses following the cessation of COVID-19 pandemic-related social restrictions in summer 2021. The number of diagnoses in 2022 was the highest annual number on record.

Diagnosis rates for gonorrhoea are consistently disproportionately higher in specific communities including:

those who live in the most deprived areas
people of black Caribbean ethnicity
people born in Central or South America (this measure is used as a proxy for being of Latino, Latina or Latine ethnicity)
young people 15 to 24 years of age and gay, bisexual and other men who have sex with men (GBMSM)

Of these communities the highest diagnoses rates are in GBMSM, however it should be noted that these communities are not mutually exclusive.

Natural infection does not give protection against future infections, and among both GBMSM and heterosexuals, a recent history of gonorrhoea is a reliable predictor of future reinfection with gonorrhoea or other STIs.

Meningococcal B vaccine

4CMenB is a 4-component serogroup B meningococcal vaccine that contains:

3 main Neisseria meningitidis proteins:
- Neisseria heparin binding antigen (NHBA)
- Neisserial adhesion A (NadA)
- factor H binding protein (fHbp)
meningococcal serogroup B outer membrane vesicles (OMVs)

The only licensed 4-component vaccine currently available in the UK is Bexsero® which is manufactured by GSK, and authorised for the prevention of meningococcal disease in individuals aged 2 months and older.

The 4CMenB vaccine is currently used in the routine childhood programme given at 8 weeks, 16 weeks and one year for the prevention of meningococcal disease.

Question 2

Evidence

Accepted Answer

Neisseria meningitidis and Neisseria gonorrhoeae are closely genetically related with between 80 to 90% sequence homology. This homology gives the potential for cross-protection from OMV containing meningococcal B vaccines against Neisseria gonorrhoeae.

Vaccine effectiveness against gonococcal disease

In 2004, an outbreak of meningococcal serogroup B in New Zealand prompted a universal offer of an outbreak-specific MenB OMV vaccine (MeNZB™) in children and young adults. Post-implementation surveillance identified that as well as a decline in meningococcal serogroup B infection, there was also a decline in gonorrhoea rates in adolescents and young adults who were eligible for this OMV vaccine, this suggested that the OMV vaccine may have a protective effect against Neisseria gonorrhoea due to cross-protection from shared proteins on the surface of meningococci and gonococci (Ruiz Garcia and others). Subsequently, a case-control study was carried out in STI clinics in New Zealand in individuals who had been eligible to receive OMV vaccine (MeNZB), this estimated a vaccine effectiveness of 31% against gonorrhoea (Petousis-Harris and others).

As the 4CMenB vaccine also contains the OMV used in the MeNZB vaccine, as well as NHBA which is found on the surface of both meningococcus and gonococcus, it was hypothesised that this vaccine could potentially provide even greater protection against gonorrhoea than seen for the MeNZB vaccine.

Animal studies have shown that antibodies induced by the administration of 4CMenB vaccine recognised gonococcal outer membrane proteins and accelerated clearance of the infection (Leduc and others).

Observational studies have been carried out in adolescents and young adults in Canada, Australia and the United States of America (USA) where 4CMenB has been offered and a lower incidence of gonorrhoea has been identified in vaccinated individuals compared with unvaccinated. In South Australia, a study based on their adolescent 4CMenB vaccination programme showed a 2-dose effectiveness of 32.7% against gonorrhoea after 2 years (Wang and others). In the USA, a study using STI surveillance data from New York City and Philadelphia estimated a 2-dose course of 4CMenB to have a 40% vaccine effectiveness against gonorrhoea, with a vaccine effectiveness of 26% for one dose (Abara and others 2022). In Quebec, Canada, an estimated 59% reduction in gonorrhoea cases was seen in the post-vaccination period, however results were not statistically significant due to the size of the study (Longtin and others). A 46% reduction of gonorrhoea cases was also seen following administration of 4CMenB in a retrospective study in California supporting the potential for use of 4CMenB vaccine in the prevention of gonorrhoea (Bruxvoort and others). Results from another study in Italy in GBMSM living with HIV estimated a 42% vaccine effectiveness after 2 doses of 4CMenB (Raccagni and others).

At the time of writing there are a number of other studies ongoing to examine immunogenicity and the potential vaccine effectiveness of 4CMenB in protection against gonorrhoea in adolescent or young adult and GBMSM cohorts. Data from these studies will be reviewed once available.

Evidence of protection from meningococcal serogroup B vaccines has only been observed in OMV containing vaccines such as 4CMenB and MeNZB. An observational study showed that the MenB-FHbp vaccine did not have an effect on gonorrhoea infection, and also provided evidence that this effect observed with the 4CMenB was not due to healthy vaccinee bias (Abara and others 2023).

Cost-effectiveness modelling analysis

The JCVI reviewed modelling from Imperial College and UKHSA which focused on potential vaccination of GBMSM in England aged 15 to 65 years (Whittles and others). This modelling was carried out and published prior to published estimates of vaccine effectiveness with the 4CMenB vaccine and therefore a variety of vaccine effectiveness values (20%, 40% and 80%) were modelled. Additional analyses were carried out using the Petousis-Harris and others estimates from the MeNZB vaccine study. Similarly, there are limited data available on duration of protection and therefore estimates were used based on the estimated length of protection against meningococcal B disease.

Four different vaccination scenarios were included in the model:

vaccination before entry into the sexually active population where all adolescents are vaccinated before they become sexually active
vaccination on diagnosis where GBMSM are offered vaccine following diagnosis of gonorrhoea in sexual health services
vaccination on attendance where all GBMSM attending sexual health services are offered vaccine
vaccination according to risk where GBMSM who have been diagnosed with gonorrhoea are offered vaccine as well as those who report high numbers of sexual partners

Each vaccination scenario modelled required different numbers of doses being administered with varying levels of average risk within the individuals offered vaccination:

vaccination of adolescents routinely would use the most doses of vaccine and the average risk of vaccinated individuals would be the lowest
vaccination of all those attending sexual health services would immunise individuals whose average risk is higher than the population average but not as high as those who had been diagnosed with gonorrhoea or are otherwise at increased risk
vaccination of those attending sexual health services, those who have been diagnosed with gonorrhoea and vaccinating according to risk, would all see a decline over time in the number of doses being offered because:
- vaccinating people reduces the number of people requiring vaccination
- cases of gonorrhoea are averted by a vaccination programme

Vaccinating in sexual health services on diagnosis would require the least number of doses, with vaccinating according to risk requiring more doses, and vaccination on attendance at sexual health services requiring a much larger number of doses.

Vaccinating according to risk and vaccination on attendance at sexual health services were almost identical in terms of impact of the programme with the greatest impact on cases of all the scenarios. The potential costs of a programme were closely related to the number of doses which would be administered.

When using MeNZB estimates for vaccine effectiveness, vaccinating those at risk is preferable to vaccinating only those who have been diagnosed with gonorrhoea in terms of the cost effectiveness and the health benefits. Vaccinating all those attending sexual health services only has a small incremental increased health benefit over those at risk, however it costs significantly more and would use many more doses for only a small increase in the number of gonorrhoea cases averted.

The modelling concluded that vaccinating those at risk was likely to be the most cost-effective strategy, with vaccinating those who had been diagnosed also likely to be cost-effective. Vaccinating all those attending services would only be cost-effective at a low vaccine price due to the increased number of doses required and the lower average risk of individuals.

The greatest determinants of cost-effectiveness were duration of protection and vaccine effectiveness, as well as price. The duration of protection from the vaccination against gonorrhoea remains unknown, this is important to calculate vaccine value and at what point revaccination may be needed. Increases in efficacy increase the value of a vaccine more than increases in the duration of protection.

The model assumed that benefit from vaccination was only seen after 2 doses, however there is likely to be some protection from a single dose therefore the model is likely to underestimate vaccine value. A vaccination programme is also likely to have a currently unquantifiable benefit in reduction of antimicrobial resistance.

Question 3

JCVI advice

Accepted Answer

The JCVI considered the evidence presented in terms of programme cost-effectiveness and likely impact on gonorrhoea epidemiology. The committee agreed that a targeted programme should be initiated using the 4CMenB vaccine for the prevention of gonorrhoea in those who are at greatest risk of infection.

This programme should be offered on an opportunistic basis through specialist sexual health services who have vast experience in assessment and identification of those who are at increased risk of infection with bacterial STIs.

It is important for individuals offered vaccination to understand that real world studies have estimated that the 4CMenB vaccine has between 32.7 to 42% effectiveness against gonorrhoea. Therefore, although vaccination would be expected to reduce the chance of becoming infected with gonorrhoea, it would not completely eliminate the possibility. Vaccinated individuals could expect to have some reduction in their own risk of contracting gonorrhoea, however the main benefit of a vaccination programme is expected to be at a community level with a significant reduction in the number of cases overall.

Even with a modest vaccine effectiveness, vaccination is of benefit as previous infection with gonorrhoea is thought to offer little protection against future infection and reinfection is therefore common.

As protection against gonorrhoea isn’t currently a licensed indication for 4CMenB vaccine, this advice is based on off-label use of vaccine.

Eligibility

The programme should primarily target GBMSM who are at increased risk of becoming infected. These risk criteria may include but not be limited to:

a recent history of gonorrhoea or other bacterial STI diagnosis, individuals should also be offered vaccination after a gonorrhoea diagnosis (whether symptomatic or asymptomatic)
reporting high-risk sexual behaviours with multiple partners during sexual health screening and assessment

Any offer of vaccination should be based on individual risk assessment by a sexual health clinical professional.

While a disproportionate number of gonococcal infections are within GBMSM, this doesn’t cover the entire population at risk. Efforts should be made to ensure that the vaccine is offered to those at similar risk, including but not limited to transgender women and gender-diverse people assigned male at birth. In addition, vaccination should be considered in any other people, irrespective of gender, who may be heterosexual or identify otherwise and who have equivalent markers of increased risk including but not limited to those with a recent history of bacterial STI diagnosis and sex workers.

The JCVI were not aware of any data on the administration of 4CMenB while currently infected with gonorrhoea, and there was some concern that this might lead to the vaccine being ineffective due to the failure to mount a complete immune response to an antigen during an active infection - this is known as anergy. Vaccination should therefore be delayed in those with an active infection.

As gonorrhoea rates are disproportionally high in certain key communities tied to existing health inequalities, the JCVI support efforts made by the NHS, sexual health services and other organisations involved in outreach and inreach work to ensure equitable access to vaccination in those who are most at risk.

As with all immunisation advice, the JCVI will keep this under review and the programme costs and benefits, and eligibility may be reassessed as further information about vaccine effectiveness and duration of protection becomes available.