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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 18  |  Issue : 1  |  Page : 28-35

Sexually transmitted diseases vaccines: Progress and challenges


Department of Microbiology, GIPMER, New Delhi, India

Date of Submission26-Oct-2019
Date of Decision14-Nov-2019
Date of Acceptance05-Dec-2019
Date of Web Publication03-Feb-2020

Correspondence Address:
Dr. Abha Sharma
Department of Microbiology, GIPMER, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_52_19

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  Abstract 


Many sexually transmitted diseases (STDs) such as hepatitis B virus, and human papillomavirus can be effectively prevented with vaccines. However, vaccines for other STDs (e.g., human immunodeficiency viruses (HIV), herpes simplex virus (HSV), gonorrhea, syphilis, chlamydia, etc.) are under development. Although the focus of most researchers worldwide is more on HIV vaccine development, this review focuses largely on challenges being faced and current development on vaccines against gonorrhea, syphilis, chlamydial infection, chancroid, and trichomoniasis.

Keywords: Chlamydia, gonorrhea, sexually transmitted disease vaccines, Trichomonas


How to cite this article:
Sharma A. Sexually transmitted diseases vaccines: Progress and challenges. Curr Med Issues 2020;18:28-35

How to cite this URL:
Sharma A. Sexually transmitted diseases vaccines: Progress and challenges. Curr Med Issues [serial online] 2020 [cited 2020 Feb 24];18:28-35. Available from: http://www.cmijournal.org/text.asp?2020/18/1/28/277526




  The Need for Sexually Transmitted Disease Vaccine Top


Sexually transmitted diseases (STDs) are a major public health problem worldwide. More than 1 million infections are acquired daily. An estimated 357 million new infections with 1 of 4 STDs: Chlamydia, gonorrhea, syphilis, and trichomoniasis occur annually.[1] With the HIV epidemic, STD researchers mostly focus on HIV, while curable STDs such as gonorrhea, syphilis, chancroid, and chlamydia receive less attention. In the last 10–15 years, accessible treatment clinics and public awareness in many countries have resulted in decreased incidence of STDs, particularly gonorrhea.[2],[3] In the United States increasing number of chlamydia infections have made it the most widespread STD. In 1997 rate of chlamydia infection was 205.5/100,000 population, and by 2009, it rose to 409.2/100,000 population.[4]

More than 20 pathogens exist that cause STDs. Increased susceptibility to HIV associated with STDs makes STD control an important issue.[5],[6] Genital ulcer disease (GUD) is an important cofactor for HIV transmission.[7],[8] The significant role of bacterial STDs in the transmission of HIV has led the World Health Organization (WHO) to conclude that STD control program should be developed along with the strategies to control HIV.[9] Efforts for STD control such as early disease detection, use of new antibiotics, and emphasis on behavioral intervention have not been totally successful. In general, immunizing population at risk is a highly effective method of controlling infectious diseases. Vaccines against STDs can prove to be a long-lasting and cost-effective solution of improving the public health.


  Challenges in Sexually Transmitted Disease Vaccine Development Top


An effective STD vaccine except hepatitis B virus (HBV) and human papillomavirus (HPV) is yet to be developed. STD pathogens mostly infect via the genital tract mucosa, and therefore, it is logical to develop vaccines administered via the mucosa.[10] Most researches target mucosal immunity in the gut. There is very little literature on mucosal immunity of the genitourinary tract.[10],[11],[12] The feasibility of vaccine depends on (1) nature of organism, (2) nature of infection, (3) host's ability to develop natural immunity after infection, (4) whether organism is cultivable, (5) degree of antigenic diversity, and (6) availability of suitable animal model.[10],[11],[12],[13] STD pathogens are structurally complex and confer limited immunity after infection. Furthermore, significant antigenic diversity seen in these pathogens hinders vaccine development. Humans are the only natural host for most STDs, and hence, it is difficult to find an animal model that adequately imitates all aspects of the human disease. The hope for developing STD vaccines arises with the fact that except Treponema pallidum and HPV, all STD pathogens are cultivable. The question that still needs to be answered is will such vaccines be developed? The progress and challenges associated with STD vaccines will be discussed here in this review excluding HIV, HPV, and HBV.


  Syphilis Top


Problem scenario

Syphilis is caused by bacteria T. pallidum subsp. pallidum. In 2012, the WHO estimated 5.6 million new syphilis cases among adolescents and adults aged 15–49 years with global incidence rate being 1.5/1000 cases with the highest prevalence in the WHO African region.[14] The disease is transmitted through direct contact with sores on the external genitalia and an infected pregnant woman to her unborn child.

Immunopathogenecity

Some level of acquired immunity develops during the course of syphilis, as it has been observed that only one-third of untreated cases of syphilis develop late complications of disease.[15] T-cell-mediated delayed type hypersensitivity (DTH) is the predominant immune mechanism in primary syphilis. T-cell secreting lymphokines activate macrophages to destroy infecting organism; antibody and cytotoxic T-cells (CTL) have little effect on T. pallidum in tissues.[16] Therefore, a syphilis vaccine should induce DTH rather than antibodies or CTL.[15] However, few studies have shown that both humoral- and cell-mediated immune mechanisms contribute to the resolution of lesion and control (latency) of treponemal infection, but clarifying the role of both of these arms of the immune system remains warranted.[17],[18]

Challenges and progress in vaccine development so far

Continuousin vitro cultivation of T. pallidum has not yet been accomplished, although limited propagation and single passage survival have been achieved in a tissue culture system.[14] The metabolism, physiology, and antigenic structure of T. pallidum have been studied through organisms propagated by passage in experimental animals, usually rabbits.

Potential vaccine targets

Most vaccine strategies in the past have focused on circulating antibodies, not sensitized T-cells.[16],[19] Since T. pallidum is believed to be an extracellular pathogen, its outer membrane proteins (OMPs) have been highly researched as targets for opsonic or bactericidal antibodies for vaccine development.[20] Four T. pallidum proteins Tp0155, Tp0326, Tp0483, and Tp0956 have recently emerged as potential OMP candidates.[21] However, Tomson et al.[20] in their study failed to induce immunoprotection in the rabbit model of experimental syphilis with these OMP candidates. The search for a bona fide surface exposed OMP remains paramount. A number of new approaches have become feasible for the development of effective vaccine, including purified recombinant antigens, synthetic peptide antigens, and vectored vaccines. Complete protection against infection was seen in the rabbit animal model using an extended immunization regimen of γ-irradiated T. pallidum, demonstrating the treponemal surface components in generation of protective immunity and the feasibility of syphilis vaccine development.[22] The protein TpN19 as well as TpN36 and recombinant endoflagellar protein partially protected rabbits against intradermal challenge with T. pallidum.[13] Recently, the experiments are being directed toward vectored vaccines. To induce DTH, antigens need to be presented via exogenous pathway. Bacille-Calmette-Guerin, a live-attenuated bovine tubercle bacillus, widely used to immunize against tuberculosis may prove to be an ideal vaccine vector for T. pallidum antigens, as it has the potential to induce a high level of DTH.[16] In an effort to control spread of syphilis, research still continues for the development of an ideal syphilis vaccine. None of the vaccines have reached clinical trials yet.

Latest update in vaccine development for syphilis

Adhesin Tp0751 is a T. pallidum protein that has recently been implicated in treponemal dissemination. Lithgow et al.[23] showed in their study that immunization for Tp0751 inhibits treponemal dissemination to distant organ sites thus making it a promising vaccine candidate in order to prevent hematogenous spread of syphiliswithin the host.


  Gonorrhea Top


Problem scenario

Gonorrhea, caused by  Neisseria More Details gonorrhoeae is a commonly reported STD. Worldwide, 78 million new cases are reported every year.[24] Localized infection occurs in both males and females. In males, it is usually symptomatic with purulent urethral discharge and dysuria being the hallmark of the disease. Females serve as reservoir of the disease. In females, up to 50% infection may be asymptomatic, thus delaying the diagnosis and treatment. Disseminated gonococcal infection may be a consequence of asymptomatic infection, common in females. Perinatal infection also occur which can lead to conjunctivitis in newborns. Increasing antibiotic resistance is seen in gonorrhea, with some cases left with no treatment option due to pandrug resistance. Hence, the WHO has included gonorrhea in its list of bacteria with greatest threat to human health.[24]

Immunopathogenecity

Immune response to gonococcal infection confers little immunity to reinfection, due to antigenic variation of the gonococcus and redirection of immune responses.[25] While antibodies may be demonstrated on mucosal surfaces such as IgG and IgA, they are highly strain specific with little protective ability.

Need for a gonococcal vaccine

Emergence of antibiotic resistance has increased dramatically.[26],[27] Penicillin resistance emerged in 1970s and tetracycline resistance emerged 10 years later. These antibiotics were abandoned as treatment options. Fluoroquinolones were recommended for the treatment of gonococcal infection, however, in 2006, resistance to this class of antibiotic had risen to 13.8%. Hence, the CDC announced in 2007 that fluoroquinolones were no longer the recommended therapy.[26] Now the treatment of gonorrhea is restricted to a single class of antibiotics, i.e., third-generation cephalosporins. Oral formulations like cefixime have also become less effective due to emerging resistance to cephalosporins. Reports from Southeast Asia and elsewhere show decreasein vitro susceptibility to ceftriaxone. It is expected that within a decade the resistant gonococcal isolates will increase and treatment with existing cephalosporins will no longer be useful. Hence, in addition to mortality associated with gonorrhea, the emerging antibiotic resistance and other important factors like facilitation of HIV transmission by concomitant gonococcal infection[28] have led to the need for the development of a gonococcal vaccine. It is believed that prevention of gonococcal infection by vaccination would decrease HIV transmission rates as a secondary consequence.

Challenges and progress in gonococcal vaccine development

Several challenges limit vaccine development. There is no simple animal model of mucosal disease. Chimpanzees are the only nonhuman primates capable of mucosal infection by gonococci but are expensive and difficult to work with and are now virtually unavailable for similar studies.[29] Development of the female genital tract mouse model for studies of pathogenesis of gonococci[30] opened up new possibilities for early phase studies of possible vaccines for gonococcus. The choice of mouse model for development of gonococcal vaccine is promising because of the advanced state of development of mouse genetics and excellent tools for monitoring immune response in the mouse. Like in humans, mice develop an inflammatory immune response, but no resistance to reinfection by the same strain, and no immune memory responses after genital tract infection.[31] The new transgenic mouse that expresses receptors for potential vaccine antigens are already available. Humanized mouse models are generated in multiple laboratories that may be helpful in assessing human-like immune responses in mice. Also, there is little understanding of phenotypic variationin vivo and of mucosal response to gonococcal infection and its significance.[32] The gonococcal cell surface is extremely variable, being composed of protein and polysaccharide antigens such as pilin, opacity proteins (Opa), that rapidly change in antigenic character.

Vaccines that entered clinical trials

Only two vaccines entered into clinical trials. In 1974, in a controlled experiment in Northern Canada, a crude-killed whole cell vaccine was studied with no evidence of protection; hence, it was not developed further. In 1976, CDC Atlanta scientists tested another vaccine made from piliated gonococcus strain in Chimps. It resulted in protection very similar to that observed after natural immune clearance of infection in chimps, requiring 1000-fold larger inoculum to infect vaccinated animals.

Potential vaccine targets

Significant efforts focused on purified Pil vaccine, trials on human volunteers were done resulting in no protection.[33],[34] Since 2005, there have been relatively less efforts to discover and develop common Pil epitope for use in next generation vaccine due to antigenic variation of pilin protein.[29] Other vaccine candidates are being considered but none succeeded to clinical trials. Antigens that do not exhibit antigenic variation like several outer membrane iron transport porins and lipooligosaccharide (LOS) are promising vaccine targets but are blocked by sialylation.[35],[36] Porin proteins are abundant in the outer membrane and may represent good vaccine targets if delivered in a native conformation. N. gonorrhoeae expresses one of the two porin alleles, Por B1 A (associated with disseminated infections) and Por B1B (associated with localized infections). Expression of either allele can result in serum resistance.[34] Por B protein does not show high frequency phase variation and seems to be an ideal vaccine target. Sparling et al. tested several immunization strategies with Por B. A DNA-based delivery system generated the lowest level of antibody but a booster with recombinant protein increased this level modestly. Intranasal administration of Por B containg outer membrane vesicles generated the most functional and potentially protective responses.[37] LOS is another potential vaccine candidate. However, several mechanism in gonococcus evade attack by this potential immunogen: (a) LOS core sugars mimic some host antigens that decrease the immune response, (b) subject to no phase or antigenic variation, and (c) sialylation of terminal core sugarin vitro andin vivo lessens bactericidal activities of serum antibodies, thus inhibiting complement deposition and antibody attack on both LOS and Por.[37]

In search for an ideal gonococcal vaccine, scientists have also focused on receptors that are important for nutrient acquisition like the iron transport proteins. These transferrin receptors are expressed by all gonococci and are not subjected to high frequency phase or antigenic variation. Most of the parts of transferrin binding proteins are immunogenic in mice when conjugated to or genetically fused with a detoxified form of cholera toxin. Anti-transferrin-binding protein antibodies are bactericidal and have growth inhibitory activities. Another attractive approach has been to use DNA vaccines expressing PorB, also there has been a surge in viral derivatives that deliver antigens like viral-like particles that do not replicate or as viral replicon particles (VRPs) that have single cycle of replication. Both Por B DNA vaccine and PorB VRP vaccine have appeared promising in terms of immune responses in vaccine efficacy experiments.[38]

Other promising vaccine antigens can be identified from genomic sequence data employing bioinformatics. Several candidate antigens have been identified which have shown promising results regarding immunogenicity and eliciting relevant immune responses. Recently, conserved vaccine antigens have been identified that elicit bactericidal antibodies that play key role in pathogenesis and could be targeted by a vaccine-induced response. A murine genital tract infection model is available for systematic testing of antigens, immunization routes, and adjuvants. Furthermore, mechanisms by which N. gonorrhoeae avoids inducing a protective adaptive response are being elucidated using human cells and the mouse model.[39] However, a successful gonococcal vaccine would be expected to contain one or several surface exposed antigens with important functions in vivo. The selection of a good adjuvant and delivery system is crucial to the success of any gonococcal vaccine development effort.

Latest update in vaccine development for gonorrhea

Unexpected reduced rates of gonorrhea were observed during a mass vaccination campaign (2004–2006) for an outbreak of bacterial meningitis in New Zealand. First time, a vaccine had shown any protection against gonorrhea. The outer membrane of the bacteria causing meningococcal disease was the vaccine target. It was observed by the researchers that people who received the vaccine were significantly less likely to become infected with gonorrhea than people who had not received the vaccine: 41% versus 51%.[24]


  Chlamydia Top


Problem scenario

Chlamydia trachomatis is a Gram-negative obligate intracellular bacterium and is leading cause of STD in both developed and developing countries with more than 90 million cases of genital chlamydial infection occurring annually.[1] Infection results in acute inflammation, clinically diagnosed as cervicitis in females and nongonococcal urethritis in males. However, up to 75% of females and 50% of males infected with C. trachomatis are asymptomatic.[40]

Immunopathogenecity

Clinical studies in humans and experimentation in animal models show that chlamydial immunity correlates with a strong T helper Type I (Th1) response as well as complementary antibody response that enhances immunity to reinfection. This finding has furnished important immunological correlates for vaccine testing and evaluation.[41],[42],[43]

Need for a vaccine

Chlamydia is still a major problem mainly because it causes long-term disease sequelae. A vaccination program is considered to be the cheaper and best approach to decrease the prevalence of C. trachomatis infection. Highest incidence is seen in reproductive age group; therefore, a vaccine protecting females in their fertile period would be valuable in achieving a high level of public health.

Challenges and progress in chlamydial vaccine development

Currently, no vaccines are available against C. trachomatis. An effective vaccine should be capable of inducing long-lived heterotypic protective immunity. However, there are many challenges such as the need to clearly define the relevant effectors mediating immunity, the antigens responsible for inducing these effectors, anti-chlamydial action of these effectors, and establishment of most effective method of vaccine delivery. Furthermore, the biological complexity of chlamydia, existence of multiple serovars, and the capacity to induce both protective and deleterious immune effectors plus the occurrence of asymptomatic and persistent infection further hinders the progress of development of an ideal chlamydial vaccine.[44] Some unique properties of the genital tract should be considered when developing a chlamydial vaccine. The genital mucosa, unlike other mucosal effector tissues, lacks organized lymphatics which can result in delayed systemic response relative to other sites.[45] Furthermore, female genital tract is subjected to hormonal regulation and intravaginal vaccine efficacy is influenced by the menstrual cycle.[45],[46] Hence, a C. trachomatis vaccine has to induce both mucosal and systemic protective response.

In 1960s, live and killed whole-cell organism chlamydial vaccines were tested both in humans and in nonhuman primates to protect against trachoma. A short-lived immune response and serovar-/subgroup-specific protection was observed. Furthermore, in the patients, the reexposure to C. trachomatis resulted in hypersensitivity reaction which is thought to be due to a chlamydial component present in the whole organism.[47],[48] This prompted the search for a subunit vaccine. Subunit vaccines are safer, cannot revert to a virulent form, and undesirable antigens that can induce inflammation damage can be avoided.[49] However, the disadvantage of subunit vaccine is that they are poor inducers of cell-mediated immunity which is important in defence against C. trachomatis. Furthermore, the use of adjuvants is recommended. Recent studies in mouse models have focused on utilizing Chlamydia muridarum major OMPs (MOMPs) as a subunit vaccine.[50],[51] MOMP is considered a strong candidate because of its antigenic properties with many T-cell and B-cell epitopes.[52] Immunization with native form of MOMP (nMOMP) has produced significant levels of protection in mice against genital and respiratory challenges, and in monkeys against ocular infection.[53],[54] nMOMP is very costly to use in large quantities and therefore the use of recombinant MOMP (rMOMP) is preferred although rMOMP was found to produce less protection as compared with nMOMP.[55] Recently, it has been proved that vaccination of mice with rMOMP, using a combination of mucosal priming and systemic boosting immunization routes, provides significant protection against a vaginal challenge with chlamydia. Higher fertility rates were observed compared to mucosal or systemic only immunization routes.[55]

Today, computer-based methods to predict antigenic epitopes are available which produce synthetic peptides which correspond with the important immunogenic domain on the antigens. Studies with MOMP peptides showed variable results with maximum partial protection. Some preliminary studies in mice showed that intradermal inoculation of a peptide from a conserved region of MOMP of C. trachomatis conferred some protection against development of salpingitis.[56] In contrast, Su et al.[57] found parenteral immunization of mice with an alum-adsorbed synthetic oligopeptide of C. trachomatis MOMP was ineffective in preventing chlamydial genital infection. Vaccines based on humoral immunity alone are unlikely to protect against infection caused by intracellular pathogens. For these infections, vaccines that induce cellular immune response are essential. Major challenges in developing such vaccines include difficulty in identifying relevant T-cell antigen and delivering them in ways that elicit protective cellular immunity. Therefore, DNA vaccination which induces both humoral and cellular immunity can be a promising approach for chlamydial vaccine development. The first attempt to generate MOMP-based DNA vaccine against genital chlamydia was disappointing.[58] Only modest immune response was generated with no protection against infection or disease. In 2010 and 2011, Schautteet et al.[59],[60] used a pig model for C. trachomatis MOMP-based DNA vaccine. The vaccine when administered vaginally and via nasal mucosa-elicited protective cell-mediated immunity and humoral immunity in pigs. However, infection could not be cleared completely.

Till date, no protective vaccines are available. Different immunization protocols in different trials have resulted in variable success.

Latest update for vaccine development for Chlamydia:

Recently in 2016, researchers showed that a novel chlamydial antigen known as BD584 is a potential vaccine candidate for C. trachomatis. BD584 antigen was able to reduce chlamydial shedding by 95% and decrease hydrosalpinx by 87.5%.[61]


  Chancroid Top


Problem scenario

It is an ulcerating cutaneous infection caused by Hemophilus ducreyi. It may persist for months without effective therapy. It is difficult to assess the current epidemiology of chancroid because of syndromic management of GUD and lack of reporting and diagnostic tools. The organism's ability to cause ulcers on stratified squamous epithelium suggests that itproduces cytotoxins and other extracellular products capable of destroying tissues.[37]

Immunopathogenecity

Scientists observed that live H. ducreyi injected into rabbits produce low-titer anti-cytotoxin antibodies and immunization of rabbits with crude preparation of cytotoxin results in neutralizing anti-cytotoxin antibodies.[62] The fact that cytotoxins can be used to create effective vaccines as in diphtheria, interest arises in understanding the actual role of the cytotoxins in the pathogenesis of human chancroid which still remains unclear.

Potential vaccine targets

Lundqvist et al.[63] has mentioned in his study that the bacterium produces a cytolethal distending toxin (HdCDT) causing cell cycle arrest and apoptosis of human cells and contributes to the aggravation of ulcers. They proved that induction of high antibody levels specific to HdCDT in the genital tissue of mice can be achieved by parenteral immunization with the toxoid thus making HdCDT toxoid a candidate component in vaccine against chancroid.

Challenges in chancroid vaccine development

An effective vaccine against chancroid has not been developed. Unlike most bacteria, hemophilus species are unable to synthesize heme, the iron-containing component of hemoglobin, and obtain it from host hemoglobin. The researchers found that immunizing swine with a purified Hb receptor protected the animal from a challenge infection. Blood tests showed that the immunized pigs formed antibodies that prevented the organism from binding hemoglobin and hence, obtaining the heme it needs to survive. In skin biopsies of the immunized animal, researchers found no viable chancroid bacteria.[64] Recent studies[65],[66] on immunization with H. ducreyi HbA receptor with adjuvants approved for use in humans have shown promising results with chancroid vaccines in pigs; and therefore, it is thought that may be developing a chancroid vaccine would be a simple and easy task in the near future.


  Trichomoniasis Top


Problem scenario and need for vaccine

Infection with Trichomonas vaginalis is common in developing countries. Although treatment is available, infection is often asymptomatic and goes untreated, creating reservoirs of T. vaginalis, thus helping disease spread. Moreover, metronidazole is the standard treatment for trichomoniasis and metronidazole resistant T. vaginalis has been impilicated in increasing number of refractory cases. Hence, a vaccine would be desirable given the widespread occurrence and impact of the disease.

Immunopathogenecity

T. vaginalis infection does not induce long-term immunity. The antibody response includes circulating serum and cervicovaginal IgA, IgG, and IgM with limited protection. Soon antibody titers decrease making host prone to reinfection.

Potential vaccine candidates

Research in vaccine development for T. vaginalis is promising. Potential vaccine candidates are 115 KDa α actin protein, adhesions, mucinases, and cystein-proteinases.[67] These antigens have common antigenic epitopes implicating possible cross-isolate protection.

Vaccines that entered clinical trial phase

Two vaccines entered clinical trials. The first studied in 1960s, 100% clinical improvement was noted in a trial of 100 women with refractory trichomoniasis receiving intravaginal inoculation with increasing number of heat-killed T. vaginalis cells. However, this vaccination method was left unpursued.[68] During 1970s, a lactobacillus vaccine, SolcoTrichovac was introduced[69] which contained eight inactivated aberrant strains of Lactobacillus acidophilus isolated from patients infected with T. vaginalis. However, several studies[69],[70] proved that this vaccine was more effective at resolving clinical signs than in reducing the number of parasites in the vagina and the immunotherapeutic effect was not mediated by crossreacting antibodies. A murine model of T. vaginalis was established in the 90s in which mice were immunized with whole trichomonads and showed protection. Similar murine model was developed for Tritrichomonas foetus which is a protozoan related to T. vaginalis causing vaginal infection and spontaneous abortion in cattles with similar disease mechanism. The success of the related model and launch of a successful vaccine for T. foetus raises hope for producing a T. vaginalis vaccine also.


  Conclusion Top


Vaccine development for STDs should be directed mainly toward gonorrhea, syphilis, and chlamydia because serious morbidity and sequelae are associated with these STDs. Research on STD vaccines is still ongoing, and till date, no vaccine has been able to enter clinical trials [Table 1].[71],[72],[73],[74],[75] Stimulating long-term immunity in the genital tract remains a challenge due to insufficient knowledge about genital tract immunology, and more research is the need.Prospects appear best for a MOMP-based chlamydial vaccine and T-cell antigen vaccine, followed by gonococcal vaccine based on porin proteins.Development of polyvalent vaccines by synthetic peptide technology or recombinant DNA methods appears as the best approach for STD vaccine development.Issues such as lack of good animal models and vaccine delivery systems for most of these infections need to be addressed.
Table 1: Sexually transmitted diseases vaccine research in pipeline

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Conflicts of interest

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The Need for Sex...
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Syphilis
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