Full analysis of French STI study dashes hopes for a gonorrhoea vaccine

A year ago, the DoxyVAC study’s interim results raised hopes that by combining post-exposure prophylaxis using the antibiotic doxycycline (‘doxyPEP’) with a candidate vaccine against gonorrhoea, cases of all three of the most important bacterial sexually transmitted infections could be substantially reduced in gay and bisexual men.

The final analysis of the study, however, presented at this year’s Conference on Retroviruses and Opportunistic Infections (CROI 2024) today by Professor Jean-Michel Molina of the Hôpital St Louis in Paris, found lower efficacy against gonorrhoea in both doxyPEP and vaccine recipients, and a rise in doxycyline resistance among PEP users who did catch gonorrhoea. This would seem to limit the usefulness of these preventative measures against gonorrhoea.

The randomised phase of the DoxyVAC study was stopped early in September 2022 after results from the DoxyPEP study were announced. This US study had reported an overall efficacy of 66% for doxycycline PEP against all three STIs – chlamydia, syphilis and gonorrhoea – and this headline figure is often quoted as doxyPEP’s overall efficacy.

This is misleading; in fact its efficacy against chlamydia and syphilis in HIV-negative men was 88% and 87%, respectively (in HIV-positive men it was a bit lower), but against gonorrhoea was only 55%. Preventing half of infections with a bacterium that (in a small minority of cases) can cause serious effects ranging from arthritis through heart defects to sterility was thought to be worth pursuing, though.

However, an earlier French study had found zero efficacy for doxyPEP against gonorrhoea, apparently because the proportion of gonorrhoea bacteria resistant to doxycycline was higher in France.

So, for the DoxyVAC study, Professor Molina and colleagues added, in addition to a doxycycline pill to be taken up to 72 hours after every possible exposure, a meningitis B vaccine, 4CMenB or Bexsero, given as two shots in the first two months after enrolment. The gonorrhoea bacterium is closely related to the one that causes meningococcal meningitis, and previous studies had indicated a possible efficacy against gonorrhoea of 33-40%.

The interim analysis looked at the incidence of the three STIs in 502 trial participants. It did not look at the combined efficacy of doxyPEP plus the vaccine in participants given both interventions. This was partly because the researchers did not expect doxyPEP to have significant efficacy against gonorrhoea and partly because they wanted to consider the vaccine’s efficacy in isolation. So the results against gonorrhoea were issued as two separate comparisons – doxyPEP versus no doxyPEP, and vaccine versus no vaccine.

Unexpectedly, doxyPEP did appear to have significant efficacy against gonorrhoea in the interim analysis, as did the vaccine, so there was cautious optimism that the two interventions together might provide useful protection against gonorrhoea.

However, the results of a larger final analysis presented today at CROI 2024 have largely dashed these hopes. Although the efficacy of doxyPEP against chlamydia and syphilis has been confirmed, the efficacy of both doxyPEP and the vaccine against gonorrhoea is lower than initially thought.

When preparing the final analysis, the researchers identified some discrepancies compared to their interim results – with a number of gonorrhoea infections having been omitted. In addition, the final analysis included 545 study participants (rather than 502), but more significantly they had up to 21 months of follow-up data rather than the 12 months in the interim analysis. This means that infections acquired later in the study have made a difference to the results.

The makeup of the study population is little changed in this analysis: they were largely gay and largely of French nationality with an average ago of 40. They had to be already taking HIV PrEP, with an average time on PrEP of nearly three years. There were high rates of STIs in the year before enrolment in participants, with 68% having had gonorrhoea, 49% chlamydia and 21% syphilis. In the month before joining the study, they averaged one act of condomless anal sex per week, and they had had an average of 10 partners in the last three months. Twenty-two per cent had used chemsex drugs at their last encounter.

The efficacy of doxyPEP against chlamydia and syphilis was little changed in the final analysis. The annual incidence of chlamydia was 42% in participants not on doxyPEP and 6% in people on doxyPEP, indicating 86% efficacy, where the interim analysis had found 89% efficacy. With syphilis, the efficacy was the same in interim and final analyses, at 79%. In other words, doxyPEP stopped four out of five syphilis infections that would otherwise have occurred and almost nine out of 10 chlamydia infections.

The efficacy of doxyPEP against gonorrhoea was, however, reduced in the final analysis. The interim analysis found 41% annual incidence of gonorrhoea in participants not on doxyPEP versus 20.5% in the doxyPEP arm, equating to an efficacy of 51%; this halving of gonorrhoea infections through doxyPEP alone looked very useful.

Because the follow-up period in the final analysis is considerably longer, however, later gonorrhoea infections made a difference. While the incidence rates between the two arms diverged in the first six months of the study, after that they were essentially the same – the graph showing cumulative infections after this point shows two parallel lines. Ultimately the incidence of gonorrhoea was 68% in the non-PEP arm and 45.5% in the PEP arm, implying an efficacy of 33%. This was still statistically significant (p = 0.003) but clearly of less clinical relevance.

This was compounded by the efficacy of the vaccine being considerably lower in the final analysis than in the interim analysis. In the interim analysis, 54 people were infected in the no-vaccine arm and 36 in the vaccine arm. The annual incidence of gonorrhoea, when vaccine versus non-vaccine participants were compared, discounting any effect of PEP, was 33% – already at the lower limit of expected efficacy, but still useful.

But in the final analysis there were 103 infections in participants receiving the vaccine versus 122 in ones who did not, for an annual incidence of 58% versus 77%. This equates to an efficacy of just 22%, which just fails to be statistically significant (p = 0.061). There was no interaction between the effects of doxyPEP and the vaccine; in other words, men who received doxyPEP and the vaccine were no less likely to acquire gonorrhoea than people who received doxyPEP but not the vaccine, and vice versa.

During questions and answers, Professor Molina noted that the researchers had chosen gonorrhoea infection (as identified on a PCR test) as the outcome that they would judge the effectiveness of the vaccine by. It remains plausible that the vaccine is more effective in reducing the severity of gonorrhoea disease, and if the study outcome had been symptomatic infection, the results may have been more positive.

The interim analysis had found that all of a small number of samples of bacteria from people presenting with incident gonorrhoea at baseline had low-level resistance to doxycycline, but that it was not sufficient to stop the drug working. However, in 31 samples taken from doxyPEP users and 40 from non-doxyPEP users who acquired gonorrhoea during the study, 35.5% of those taking PEP had high-level resistance that could impact on efficacy (33% in the interim analysis) and 12.5% of those not taking PEP (19% in the interim analysis). No significant resistance was found in chlamydia samples, though only a small number were taken from people on doxyPEP (as there were far fewer infections).

Professor Molina commented: “DoxyPEP is less effective against gonorrhoea, with increased rates of high level resistance to tetracyclines over time suggest effectiveness may wane over time”.

As for the vaccine: “Though a small benefit cannot be ruled out, its clinical relevance seems very limited.” A more effective vaccine is needed, and trials of a different candidate vaccine have begun.