Future Prospects for New Vaccines Against Sexually Transmitted Infections

Sami L. Gottlieb; Christine Johnston


Curr Opin Infect Dis. 2017;30(1):77-86. 

In This Article

Sexually Transmitted Infection Vaccine Development

The current status of the development pathway for STI vaccines is shown in Fig. 1. HSV vaccine candidates are furthest along in the pathway, with several candidates in Phase I and II trials.[22] For years, genital chlamydia vaccine development was firmly in the preclinical stage; however, the first Phase I human clinical trials started in 2016, and others may soon follow.[23] Vaccine development for gonorrhea and syphilis is in earlier stages, but renewed commitment to these pathogens could result in new candidates over the next several years. Understanding prospects for vaccine development for trichomoniasis will require better epidemiologic, natural history, and basic science data, and will not be discussed in detail in this review.[24]

Figure 1.

Research and development pipeline for STI vaccines. Five vaccine candidates, four for HSV [31–35] and one for CT [47,54], are in Phase I or II clinical studies. Multiple additional HSV and CT vaccine candidates are being evaluated in preclinical/animal studies; the main types of candidates or vaccine approaches are presented. Vaccine development for NG and TP is at earlier stages in the pathway; key strategies for developing viable candidates are highlighted. More data are needed to understand the path toward TV vaccine development. No current vaccine candidates are in Phase III clinical trials, but information from previous trials is provided (dotted line) [29]. MOMP, major outer membrane protein; OMV, outer membrane vesicle

Herpes Simplex Virus

HSV-2 is the most common cause of genital herpes, with an estimated 417 million people aged 14–49 infected worldwide.[10] In addition, 140 million adults are estimated to have genital infection with HSV-1, which is often acquired orally in childhood but is now an important cause of genital herpes in many high-income countries (HICs).[25] Genital HSV infection leads to chronic infection with a lifelong reservoir in the sacral ganglia. Viral reactivation occurs frequently, particularly for HSV-2, leading to recurrent genital ulcers or asymptomatic viral shedding at the genital skin or mucosa, during which HSV can be transmitted. A major negative public health consequence of HSV-2 infection is its role in propagating the HIV epidemic, as chronic genital inflammation from HSV-2 increases HIV acquisition risk by two-fold to three-fold.[15] In Kenya, the estimated population attributable fraction of HIV infection due to HSV-2 is 48%.[26] Mother-to-child HSV transmission causing neonatal herpes is rare but often leads to infant death or devastating neurologic damage. Prevention tools including antivirals and condoms can partially reduce HSV transmission risk for individuals, but no method provides adequate protection, and an HSV vaccine is a much needed prevention strategy.

Two strategies are being pursued for HSV-2 vaccine development. The classic approach uses a prophylactic vaccine targeting people who are not infected to prevent HSV acquisition. Alternatively, a therapeutic vaccine is designed for people who already have HSV-2 infection to reduce shedding and recurrences. Whether these two approaches will require different types of immunologic responses is unknown. Both neutralizing antibody responses and cell-mediated immunity may be important for a prophylactic vaccine,[27] whereas stimulation of recently described tissue-resident memory T cells is likely essential for therapeutic vaccination.[28] Several adjuvanted subunit vaccines targeting HSV glycoprotein D2 (gD2) with or without glycoprotein B2 (gB2) have been tested in Phase III clinical trials as prophylactic vaccines. Despite eliciting strong neutralizing antibody responses, none prevented HSV-2 acquisition. The most recent trial (Herpevac), which tested an adjuvanted gD2 vaccine in HSV-1/HSV-2-seronegative women, failed to prevent symptomatic genital herpes disease overall.[29] However, this vaccine did prevent genital herpes due to HSV-1, with a vaccine efficacy of 58%. Increasing antibody titers to gD2 were associated with increased vaccine efficacy against HSV-1, providing the first immune correlate of protection.[30] Although these secondary findings are promising, investment in prophylactic HSV vaccine development has declined following the results of these studies.

In contrast, the past 5 years has seen intense interest in development of a therapeutic HSV-2 vaccine, with multiple novel platforms and adjuvants under evaluation (Fig. 1). Three such candidates are currently in Phase II trials. The most advanced, GEN-003, is a subunit vaccine containing a deletion mutant of gD2 and a portion of infected cell protein 4 (ICP4), with Matrix-M2 adjuvant. In a Phase I/IIa study, participants receiving the most efficacious dose of GEN-003 had a 50% decrease in viral shedding and a 65% decrease in days with genital lesions, persisting for 12 months postvaccination.[31] T cell and antibody responses to gD2 and ICP4 also remained elevated for 12 months.[32] A second Phase II trial is evaluating an optimized formulation of GEN-003. Another candidate, VCL-HB01, is a DNA vaccine containing two codon-optimized genes (gD2+VP11/12) with Vaxfectin adjuvant. In a Phase I/II study among HSV-2-seropositive people, VCL-HB01 did not meet the primary endpoint of decreased HSV shedding, but vaccine recipients had a 57% decrease in lesion frequency at 9 months and reduction in quantity of virus detected.[33] The vaccine also induced UL46-specific T cell responses. Another DNA vaccine candidate, COR-1, contains codon-optimized gD2 and ubiquitin-fused truncated gD2 to enhance generation of cytotoxic T cells. COR-1 was safe in HSV-1/2-seronegative participants in a Phase I study and induced gD2-specific T cell but not antibody responses.[34] Results of a Phase II evaluation of COR-1 are forthcoming.

In earlier stages of development, HSV529 is a novel live, replication-defective HSV-2 with deletions in UL5 and UL29, which reduced mortality, genital disease severity, and viral shedding in animal models.[35] Phase I testing of HSV529 in HSV-2-seropositive and HSV-2-seronegative people and evaluation of genital immune responses is ongoing. All of these vaccine studies are providing valuable information about immunity to genital HSV and insights into optimal trial design for future Phase III trials. Current vaccine candidates target HSV-2, but identification of cross-reactive epitopes against HSV-1 and HSV-2 raise the possibility that a vaccine targeting both HSV types could be developed.[36] In addition, genomic sequencing of HSV-2 from different regions, revealing many highly conserved antigens, could ensure a geographically unrestricted vaccine.[37]

Chlamydia Trachomatis

Genital chlamydia infection is a concern in all world regions, with an estimated 131 million incident cases globally in 2012.[11] Young people, and adolescents in particular, are disproportionately affected.[38] Without treatment, chlamydia can ascend to the upper genital tract in women to cause acute pelvic inflammatory disease (PID), which can in turn lead to longer-term complications including tubal factor infertility, ectopic pregnancy, and chronic pelvic pain. The vast majority of chlamydia infections are asymptomatic and because tests are lacking in many settings, especially in LMICs, most infections are not diagnosed. Even when tests are available, chlamydia screening programs have had difficulty achieving high coverage levels in HICs,[39] do not appear to have reduced chlamydia transmission,[40] and even in the best case scenario might be expected to prevent only about 60% of chlamydia-related PID.[41] Recent comprehensive models suggest that every 1000 chlamydia infections result in five women with tubal factor infertility in HICs.[41] Given the estimated 68 million chlamydial infections among women each year,[11] the global burden of chlamydia-related sequelae is likely substantial.

Fortunately, development of chlamydia vaccines is advancing. A wealth of animal data and several human studies show that natural infection results in short-lived partial protective immunity.[42,43] In one study, women whose chlamydial infections cleared spontaneously between testing and treatment were less likely to become re-infected on follow-up.[44] The precise mechanisms of immunity are not completely understood, but interferon-γ (IFN-γ)-producing CD4+ T cells play a critical role, and tissue-resident memory T cells may be particularly important for vaccine development.[45,46] Antibodies play some role, whether from enhancement of Th1 effector responses or direct pathogen neutralization.[47] Novel antigens for chlamydial vaccine development have been identified through reverse vaccinology approaches, which start with computer-based analysis of the whole genome to predict likely vaccine targets, and immunoproteomics, which involves high-throughput evaluation of large protein sets to investigate antigens interacting with the host immune system.[48–50] Immune profiling of well-characterized clinical cohorts has further clarified potential vaccine targets.[51] Genetic manipulation of C. trachomatis,[52] combined with work on novel adjuvants and delivery systems,[53] is also expanding the list of vaccine candidates.

The main vaccine approaches include subunit vaccines based on the chlamydial major outer membrane protein (MOMP), whole inactivated vaccines, and live attenuated vaccines. A recombinant MOMP subunit vaccine candidate promoted strong neutralizing antibody titers and Th1 responses and showed protection against vaginal chlamydial infection in mini-pigs and against upper genital tract disease in mice.[47,54] This candidate entered human Phase I clinical trials in 2016.[23] Combination of MOMP with polymorphic membrane proteins identified by immunoproteomics is another promising approach.[49] A major advance in the field has been the ability to generate vaccine-induced seeding of genital mucosa with CD4+ tissue-resident memory T cells, which was the key to long-lived protection against chlamydial infection in mice:[46] This was achieved using mucosal immunization with UV-inactivated C. trachomatis combined with a novel nanoparticle-based adjuvant.[46] An attenuated plasmid-free chlamydial strain being evaluated as a vaccine against ocular C. trachomatis infection (trachoma) may also inform vaccine development for genital infection.[55]

Neisseria Gonorrhoeae

STI control strategies based on prompt antibiotic treatment for symptomatic patients and focused partner management have been effective at reducing the incidence of gonorrhea.[56] However, increasing evidence of resistance to cephalosporins, the only remaining first-line drugs for gonorrhea,[57] reports of multidrug resistance,[58] and progressive resistance to sequential antibiotics[16] create an urgent need for new prevention strategies. A high burden of gonorrhea exists in many LMICs, with an estimated 78 million incident infections globally in 2012:[11] In addition, there has been a resurgence of gonorrhea incidence in many HICs, especially among men who have sex with men.[8] Genital gonorrhea has adverse outcomes similar to those of chlamydia, such as PID and infertility, but there is even more limited understanding of the burden of gonorrhea-related sequelae globally. Thus, the potential threat of untreatable gonorrhea with expanding antimicrobial resistance makes vaccine development crucial.

Many biological challenges exist to gonococcal vaccine development. There is no naturally acquired immunity to the infection; N. gonorrhoeae has a highly antigenically variable surface and is well adapted to evade host responses, and robust animal models to study the infection are limited.[59] Multiple potential gonorrhea vaccine targets have been identified based on their relative antigenic conservation and stability among strains,[60] but these have not yet yielded viable vaccine candidates. However, more sophisticated mouse models are now available to evaluate immune responses and disease in a way that more closely mimics human infection.[61] In addition, new high-throughput techniques such as proteome mining, which uses bioinformatics to select proteins with desired characteristics from large datasets, have narrowed the search for promising antigenic targets:[62] Translational studies applying molecular techniques to clinical specimens allow assessment of genes expressed during gonococcal infection.[63]

A promising development for gonococcal vaccine discovery relates to existing vaccines against another Neisseria species, in particular the group B meningococcal vaccine using the outer membrane vesicle (OMV) antigen presentation strategy. N. gonorrhoeae and N. meningitidis share 80–90% homology of primary sequences and thus some level of cross-protection is plausible. A recent case–control study in New Zealand, wherein group B OMV meningococcal vaccine has been used for years, suggests a decrease in gonorrhea infection in those who have received the OMV meningococcal vaccination.[64] Expanding upon this platform could provide a template for a successful gonococcal vaccine or a broader Neisseria vaccine incorporating gonococcal antigens.

Treponema Pallidum

Syphilis incidence has decreased globally[11] but remains an important cause of fetal and neonatal mortality in many LMICs, with over 200 000 fetal and neonatal deaths estimated annually.[12,65] In addition, in several HICs with very low syphilis rates, there has been a resurgence in syphilis incidence, especially among men who have sex with men.[66] A main goal of the new Global Health Sector Strategy for STIs, 2016–2021, is to reduce global syphilis incidence by 90% by 2030.[67] However, most syphilis control programs in LMICs focus on preventing congenital syphilis through antenatal screening and treatment. It has been less clear how to reduce population-wide incidence, especially with barriers to effective partner treatment programs in resource-poor settings. These challenges are compounded by new concerns about supply chain shortages of benzathine penicillin, the only first-line treatment for syphilis.[68] These considerations have led to renewed interest in syphilis vaccine development.

Few investigators work on syphilis vaccine development, primarily due to lack of consistent funding and difficulties using the existing rabbit model of infection.[69] In the early 1970s, rabbits given multiple injections of irradiated T. pallidum over many weeks became immune to disease on subsequent challenge.[70] Although the immunization regimen used was not tenable for humans, this provided proof of concept that protection against syphilis is possible. Current efforts focus on reverse vaccinology and targeted functional studies to identify antigens important for pathogen–host interactions and pathogenesis.[71,72] Sequencing circulating syphilis strains provides additional information on potential cross-protection across selected targets.[73] The challenge now is to generate the right combination of these potential vaccine targets, with appropriate adjuvants, to develop a viable syphilis vaccine candidate.[74]