Carolyn Deal

Efficacy Results of a Trial of a Herpes Simplex Vaccine

BACKGROUND Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. METHODS We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. RESULTS The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). CONCLUSIONS In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.).

From the NIH: proceedings of a workshop on the importance of self-obtained vaginal specimens for detection of sexually transmitted infections.

On June 27, 2006, the NIH conducted a workshop to review published data and current field practices supporting the use of self-obtained vaginal swabs (SOVs) as specimens for diagnosis of sexually transmitted infections (STIs). The workshop also explored the design of studies that could support FDA clearance of SOVs for STI testing, particularly for specimens collected in nonclinical settings including patients’ homes. This report summarizes the workshop findings and recommendations. Participants concluded that self-obtained vaginal swabs are well accepted by women of all ages and that SOVs perform as well as or better than other specimen types for Chlamydia trachomatis and Neisseria gonorrhoeae detection using transcription-mediated amplification. In addition, workshop participants recommended the validation of SOV testing by public health practitioners and manufacturers of STI diagnostic tests to expedite incorporation of SOVs as a diagnostic option in clinical and nonclinical settings for Chlamydia trachomatis and Neisseria gonorrhoeae testing. Similarly, SOVs should be explored for use in the diagnosis of other sexually transmitted pathogens.

Bacterial vaginosis: identifying research gaps proceedings of a workshop sponsored by DHHS/NIH/NIAID.

The microbiota of the human vagina can affect the health of women, their fetuses, and newborns. Bacterial vaginosis (BV) is the most prevalent form of vaginal infection in women of reproductive age, affecting 8% to 23%, and is the most common etiology of vaginal symptoms prompting women to seek medical care. While traditional cultivation has identified numerous BV-associated bacteria involved in these processes, recent advances in molecular biology have facilitated the detection and identification of bacteria without cultivation, some of which have not previously been described or well characterized. A more complete understanding of vaginal microbial populations resulting from the adoption of molecular tools may lead to better strategies to maintain healthy vaginal microbial communities—thus enhancing womens health—and will create opportunities to explore the role of novel bacteria in reproductive tract diseases. On November 19–20, 2008, the NIH convened a workshop of experts in the field of research and clinical practice related to BV in order to discuss how these new advances should be interpreted and applied to research in progress and collaborations between relevant disciplines. This paper summarizes the presentations of this workshop and outlines general recommendations arising from the related discussions. Future studies of BV and its associated adverse outcomes should determine if specific combinations of organisms are more pathogenic than others, and causally associated with different adverse events. Moreover, determination of causality will depend not only on more precise categorization of the vaginal microbiota, but also on variations in the host environment that may be associated with changes in bacterial communities over time. In this report, we offer suggestions and recommendations that we hope will facilitate conduct of consistent approaches to collaborative efforts towards advancing our understanding of the vaginal microbiota and its impact on human health.

Experimental Gonococcal Infection in Male Volunteers: Cumulative Experience with Neisseria gonorrhoeae Strains FA1090 and MS11mkC.

Experimental infection of male volunteers with Neisseria gonorrhoeae is safe and reproduces the clinical features of naturally acquired gonococcal urethritis. Human inoculation studies have helped define the natural history of experimental infection with two well-characterized strains of N. gonorrhoeae, FA1090 and MS11mkC. The human model has proved useful for testing the importance of putative gonococcal virulence factors for urethral infection in men. Studies with isogenic mutants have improved our understanding of the requirements for gonococcal LOS structures, pili, opacity proteins, IgA1 protease, and the ability of infecting organisms to obtain iron from human transferrin and lactoferrin during uncomplicated urethritis. The model also presents opportunities to examine innate host immune responses that may be exploited or improved in development and testing of gonococcal vaccines. Here we review results to date with human experimental gonorrhea.

Correlate of Immune Protection Against HSV-1 Genital Disease in Vaccinated Women

BACKGROUND Previously we conducted a double-blind controlled, randomized efficacy field trial of gD-2 HSV vaccine adjuvanted with ASO4 in 8323 women. Subjects had been previously selected to be seronegative for HSV-1 and HSV-2. We found that vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease. METHODS To better understand the results of the efficacy study, post-vaccination anti-gD-2 antibody concentrations from all HSV infected subjects and matched uninfected controls were measured. Three models were used to determine whether thes responses correlated with protection against HSV infection or disease. Similarly, cellular immune responses from a subset of subjects and matched controls were evaluated for a correlation with HSV protection. RESULTS Antibodies to gD-2 correlated with protection against HSV-1 infection with higher antibody concentration associated with higher efficacy. Cellular immune responses to gD-2 did not correlate with protection. CONCLUSIONS The protection against HSV-1 infection observed in the Herpevac Trial for Women was associated with antibodies directed against the vaccine. Clinical Trials Registration NCT00057330.

The Efficacy and Safety of Gentamicin Plus Azithromycin and Gemifloxacin Plus Azithromycin as Treatment of Uncomplicated Gonorrhea

BACKGROUND Ceftriaxone is the foundation of currently recommended gonorrhea treatment. There is an urgent need for backup treatment options for patients with cephalosporin allergy or infections due to suspected cephalosporin-resistant Neisseria gonorrhoeae. We evaluated the efficacy and tolerability of 2 combinations of existing noncephalosporin antimicrobials for treatment of patients with urogenital gonorrhea. METHODS We conducted a randomized, multisite, open-label, noncomparative trial in 5 outpatient sexually transmitted disease clinic sites in Alabama, California, Maryland, and Pennsylvania. Patients aged 15-60 years diagnosed with uncomplicated urogenital gonorrhea were randomly assigned to either gentamicin 240 mg intramuscularly plus azithromycin 2 g orally, or gemifloxacin 320 mg orally plus azithromycin 2 g orally. The primary outcome was microbiological cure of urogenital infections (negative follow-up culture) at 10-17 days after treatment among 401 participants in the per protocol population. RESULTS Microbiological cure was achieved by 100% (lower 1-sided exact 95% confidence interval [CI] bound, 98.5%) of 202 evaluable participants receiving gentamicin/azithromycin, and 99.5% (lower 1-sided exact 95% CI bound, 97.6%) of 199 evaluable participants receiving gemifloxacin/azithromycin. Gentamicin/azithromycin cured 10 of 10 pharyngeal infections and 1 of 1 rectal infection; gemifloxacin/azithromycin cured 15 of 15 pharyngeal and 5 of 5 rectal infections. Gastrointestinal adverse events were common in both arms. CONCLUSIONS Gentamicin/azithromycin and gemifloxacin/azithromycin were highly effective for treatment of urogenital gonorrhea. Gastrointestinal adverse events may limit routine use. These non-cephalosporin-based regimens may be useful alternative options for patients who cannot be treated with cephalosporin antimicrobials. Additional treatment options for gonorrhea are needed. Clinical Trials Registration. NCT00926796.

Current and future treatment options for gonorrhoea

The delivery of effective antimicrobial therapy is essential for public health control of gonorrhoea, in the absence of a suitable vaccine. The antimicrobial agent chosen should have high efficacy and quality, lack toxicity and give >95% success when given empirically. Guidelines, which are informed by surveillance data, are used to aid clinicians in their choice of appropriate agent. Historically, gonorrhoea treatment has been delivered as a single, directly observed dose but this has resulted in failure of successive antimicrobial agents which have been replaced by a new antimicrobial to which resistance has been rare or non-existing. Following the drift towards decreased susceptibility and treatment failure to the extended spectrum cephalosporins, and the lack of ‘new’ alternative antimicrobials, the threat of difficult to treat or untreatable gonorrhoea has emerged. The challenge of maintaining gonorrhoea as a treatable infection has resulted in national, regional and global response or action plans. This review discusses different approaches to the future treatment of gonorrhoea including; use of ceftriaxone, the injectable cephalosporin at increased dosage; dual antimicrobial therapy; use of drugs developed for other infections and use of older agents, directed by rapid point of care tests, to susceptible infections. Finally, it is considered whether the time is right to readdress the possibility of developing an effective gonococcal vaccine, given the major advances in our understanding of natural infection, molecular pathogenesis and the revolution in molecular biology techniques.

Vaccine research for gonococcal infections: where are we?

Gonorrhoea continues to seriously impact human society with an estimated 106 million new infections occurring annually. The consequence of gonorrhoea on reproductive and neonatal health is especially concerning as is its role in the spread of HIV. Current control measures rely on the identification and treatment of infected individuals and their sexual contacts. The success of this strategy, which is already inadequate, is lessened by poor diagnostic capabilities in many parts of the world and challenged by the rapid emergence of antibiotic-resistant strains. The potential of untreatable gonorrhoea is now real, and a gonorrhoea vaccine is seriously needed. Historically, gonorrhoea vaccine research has been hampered by the antigenic variability of the gonococcal surface, a lack of known protective mechanisms, and the absence of a small laboratory animal model for testing candidate vaccines and manipulating host responses. Here we discuss recent advances that have rekindled research efforts towards a gonorrhoea vaccine. Several conserved and semiconserved vaccine antigens have been identified that elicit bactericidal antibodies or inhibit target function. A mouse genital tract infection model is available for systematic testing of vaccines, and transgenic mice have been developed to relieve host restrictions. Additionally, several immunological advances have been made including the identification of mechanisms by which Neisseria gonorrhoeae suppresses the adaptive response and the demonstration that Th1 responses clear experimental infection in mice and induce a protective memory response. We also discuss important issues with respect to product development that must be considered when entering the vaccine pipeline.

Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines

Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.

Summary and recommendations from a National Institute of Allergy and Infectious Diseases (NIAID) workshop on "Next Generation Herpes Simplex Virus Vaccines".

At a NIAID workshop entitled “Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities” on October 22–23, 2012, researchers agreed that there was a great medical need for a herpes simplex virus (HSV) vaccine and recommended increased focus on all stages of herpes vaccine research, development, and testing, including basic vaccine discovery research, development and manufacturing of vaccines, human immunology, and clinical trials. While the need for an HSV vaccine has been recognized for decades, in the last 17 years only recombinant HSV glycoprotein D (gD) alone or with gB has been tested in randomized, double-blind, placebo controlled human trials to prevent genital herpes. In 2012 the results of the Herpevac Trial for Women, the largest HSV vaccine trial to date, involving over 8,000 women who were seronegative for HSV-1 and HSV-2 were reported. The vaccine failed to reach its primary endpoint, reduction in occurrence of genital herpes disease due to either HSV-1 or HSV-2. While there was modest reduction in HSV-1 genital disease, there was no reduction in HSV-2 genital disease. The goal of the meeting was to reassess the status of the field, identify gaps in knowledge, and propose new approaches and solutions to fill the gaps. The medical need for a herpes vaccine was summarized as: Morbidity caused by herpes infections. There are 500,000 cases of oral herpes and 300,000 cases of genital herpes each year in the US. These include 20,000 cases of ocular herpes and 1,500 cases of central nervous system disease. Acute herpetic disease causes discomfort and psychological burden in immunocompetent individuals, but serious disseminated disease can occur in immunodeficient or immunosuppressed individuals. The burden of HSV-2 infection is greatest among African-Americans with 59% infected by the ages of 40–49, indicating an important health disparity. Risk of vertical transmission to neonates. There are 1,500 cases of neonatal herpes each year in the US. Neonates infected during delivery continue to have life-threatening disease, and this increases the need for Cesarean sections in mothers with new genital herpes infection. Increased risk of HIV infection. The risk of transmission of HIV-1 is increased by 4-fold if the HIV-infected individual is HSV-2 seropositive and the risk of acquisition of HIV-1 is increased by 2–3 fold if the HIV-uninfected individual is HSV-2 seropositive. Thus, an effective HSV vaccine should help to reduce the spread of HIV. Another indirect approach to reducing HIV infection, male circumcision, has previously shown to be effective. The challenges facing development of next-generation herpes vaccines that were identified and the recommendations proposed to address these were as follows: The participants identified difficulties in comparison of the results of vaccine studies and immunologic assays between different investigators due to a lack of standardized reagents and assays, including an HSV antibody neutralization assay. Efforts should be made to develop standardized reagents for preclinical vaccine development including challenge virus stocks, immunogens, adjuvants, and sera with known HSV neutralizing activity. These reagents should be made broadly available to the research community. NIAID’s Resources for Researchers program offers a variety of resources that can be explored for this purpose. (http://www.niaid.nih.gov/labsandresources/resources/Pages/default.aspx) The participants noted that different experimental endpoints are often used to study vaccine candidates in animal models compared with the endpoints used in clinical trials in humans. They recommended that animal studies utilize endpoints that more closely match those used in clinical trials. In addition, it is known that the immune system of humans has many differences from that of small animals, and this can result in different virus-host cell interactions. The participants recommended that additional animal models be developed. These models should more closely mimic human infection and the human immune response to the virus and help to identify correlates of protection both for infection and for disease. Different vaccine candidates should be compared in animal models. In particular, comparisons should be made with vaccines that have already been tested in human clinical trials, rather than simply with placebos. Efforts should be made to help facilitate the development and manufacturing of select vaccines. NIAID’s Vaccine Development Services (http://www.niaid.nih.gov/LabsandResources/resources/dmid/vaccine/Pages/default.aspx) may help to further these efforts. NIAID’s Vaccine Development Services include safety and toxicity testing, non-clinical immunogenicity and efficacy studies, process development, pilot and cGMP manufacture, and several other services. This NIAID program is designed to fill critical gaps in a product development plan. The goal is to assist the process of vaccine development by providing support which will de-risk the process at key points in order to advance products that address public health needs. The participants recognized the need for clinical testing of additional vaccine candidates, in part through the use of smaller iterative clinical trials to hone vaccine design. This would be greatly aided by developing a better understanding of the natural history of herpes infection. Several recommendations were made to assist in this effort: a Adaptive clinical trial design to accelerate the testing of more vaccine candidates. b Clinical trials in populations at high-risk for infection with HSV to obtain preliminary data on efficacy. b A laboratory infrastructure to identify immune parameters that correlate with protection from HSV disease, shedding or infection. c Design of HSV vaccine trials to capture data both on genital infection or disease and on rates of HIV acquisition or transmission. These studies could be considered for incorporation into existing clinical trial networks or sites. Perform more detailed immunologic analyses of samples from previous trials (e.g., might include the Herpevac Trial for Women). The participants felt that an HSV Vaccine Working Group should be established. This Group would be made up of researchers from academia, government, and industry to promote public-private partnerships, to decide on needed common preclinical and clinical reagents and prototype animal models, to help design clinical trials, and to promote a forum for continuing discussion of HSV vaccine development. Finally, the meeting chairs, Lawrence Corey and David Knipe, summarized that the workshop highlighted both the need and the potential for developing a safe and effective HSV vaccine. HSV offers a unique opportunity to study the host-viral interactions of a persistent viral infection in humans. Novel interactions of HSV-2 with the host have been demonstrated in both human and animal models and offer windows into new insights into the pathogenesis of this virus and host immune responses. Translating these observations into effective HSV vaccines is the challenge. The most rapid path to the optimal prophylactic and therapeutic herpes vaccines will require intensified efforts in both animal models and human studies to understand the mechanisms of immunization and identify the optimal immunogen(s), the types of immune responses induced, and the correlates of protective immunity. Increased academic, industrial, and government collaboration and partnerships are needed. Industry has highlighted the importance of “de risking” their investment, as correlates of protection for either a prophylactic or therapeutic vaccine are as yet undefined. Evaluation of novel prophylactic vaccines has potential to help stem the high acquisition rate of HSV-2 in adolescent populations in sub-Saharan Africa that poses a growing health concern. Existing clinical trials networks may offer the infrastructure to facilitate evaluation of novel vaccines. The academic community can provide the scientific leadership for such efforts. Conversely, the academic sector needs the expertise of industry to develop and manufacture novel immunogens for clinical trials. This “Global Alliance” is needed to accelerate the development of herpes vaccines. The establishment of a Herpes Vaccine Working Group and the implementation of the recommendations from the workshop will enhance the pace of research toward an efficacious herpes simplex virus vaccine.