Gonorrhea is an infection caused by the bacterium Neisseria gonorrhoeae. Transmitted primarily through sexual contact, it can infect the genital tract, rectum, and throat. With an estimated 82 million new cases globally each year, gonorrhea is one of the most common sexually transmitted infections worldwide. The urgency for a preventive vaccine has grown significantly due to the rapid emergence of antibiotic-resistant strains, which threatens to make the infection untreatable.
The Current Vaccine Status
There is currently no licensed vaccine available to prevent gonorrhea infection in humans. Prevention relies on public health strategies, including promoting safer sexual practices, widespread screening, and prompt antibiotic treatment. The development of a dedicated vaccine has been a goal for decades, with early efforts in the 1970s and 1980s focusing on whole-cell and pilus-based vaccines.
These historical attempts ultimately failed to provide durable or broad protection in human clinical trials. For instance, a vaccine targeting the gonococcal pilus, a hair-like structure on the bacterial surface, showed some initial promise against a specific strain in laboratory settings. However, it proved ineffective when tested against the diverse range of strains circulating in the population.
Biological Hurdles in Vaccine Development
The primary obstacle to creating an effective vaccine is the bacterium’s remarkable ability to change its appearance, a process known as antigenic variation. Neisseria gonorrhoeae constantly shuffles the genes for its surface proteins, such as pili and outer membrane proteins (OMPs). This rapid genetic variability means that an immune response generated against one strain may not recognize a slightly different strain, allowing for repeat infections and making it nearly impossible to select a single, consistent vaccine target.
Another significant challenge stems from the nature of the infection, which primarily occurs on mucosal surfaces, such as the urethra or cervix. Traditional intramuscular injections typically generate a strong systemic immune response, dominated by circulating IgG antibodies. However, the immune response needed to neutralize the bacterium at mucosal surfaces relies more on local immunity, including secretory IgA antibodies and specific T-cell responses. Reliably inducing this localized mucosal immunity through a standard injection remains a major hurdle for vaccine science.
Accidental Protection from the Meningitis B Vaccine
A significant finding has emerged from the use of vaccines designed to prevent Meningitis B, caused by the related bacterium Neisseria meningitidis. Since N. meningitidis and N. gonorrhoeae share 80% to 90% of their genetic material, the Meningitis B vaccine offers moderate cross-protection against gonorrhea. This effect is attributed to shared antigens, particularly those found in the outer membrane vesicles (OMVs) used in some Meningitis B vaccines, such as the four-component vaccine (4CMenB, marketed as Bexsero).
Observational studies conducted in various countries, including New Zealand and the United States, have demonstrated this effect. For example, a study in New Zealand involving a similar OMV-based Meningitis B vaccine (MeNZB) showed a protective effect of approximately 31% against gonorrhea. Subsequent meta-analyses of the 4CMenB vaccine found a pooled effectiveness ranging from 30% to 41%.
This finding has reinvigorated the entire field of gonorrhea vaccine research. It is important to note that this is an accidental, off-label effect of a vaccine licensed for a different disease, and it is not a dedicated gonorrhea vaccine. However, even this level of moderate protection could significantly impact public health by reducing the overall incidence and transmission of gonorrhea, particularly in high-risk populations.
Ongoing Research and Development
The proven concept of cross-protection has shifted the focus of dedicated gonorrhea vaccine development toward identifying and targeting conserved antigens—those surface proteins that the bacterium cannot easily change. Modern approaches, such as reverse vaccinology, analyze the entire genome of the bacterium to predict which proteins would make the best vaccine candidates based on their conservation across different strains. The goal is to create a vaccine that provides broad protection against the numerous circulating strains.
One leading modern approach involves utilizing Generalized Modules for Membrane Antigens (GMMA) technology. This method engineers modified outer membrane vesicles from N. gonorrhoeae to elicit a strong immune response against multiple antigens simultaneously, overcoming the limitation of a single target. GSK is currently advancing an investigational vaccine candidate (NgG) that has received Fast Track designation from the U.S. Food and Drug Administration (FDA). This candidate is currently in mid-stage Phase II clinical trials to assess its efficacy in healthy adults who are considered at risk for the infection.