Safety and immunogenicity of ChAd63-KH vaccine in post-kala-azar dermal leishmaniasis patients in Sudan.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6-180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.

Hepatitis B Vaccination Induces Mucosal Antibody Responses in the Female Genital Tract, Indicating Potential Mechanisms of Protection Against Infection.

Vaccines against hepatitis B virus confer effective protection. Enzyme-linked immunosorbent assay was developed to test for specific antibodies in female genital tract secretions. Anti-hepatitis B IgG and IgA were detected in the cervicovaginal secretions of women after hepatitis B vaccination, indicating a potential genital tract role for neutralizing antibodies against sexually transmitted hepatitis B virus.

Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial).

BACKGROUND: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. METHODS AND DESIGN: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three-dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 × 2 factorial trial. DISCUSSION: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost-effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. TRIAL REGISTRATION: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013).

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.

BACKGROUND: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. METHODS: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). FINDINGS: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. INTERPRETATION: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. FUNDING: MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose in young women aged 15-20 years in Kenya (KEN SHE): an immunobridging analysis of randomised controlled trials.

BACKGROUND: The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed greater than 97% efficacy against persistent HPV16 and HPV18 infection at 36 months among women in Kenya. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), the first randomised trial of the single- dose regimen in girls aged 9-14 years, the target age range for vaccination, with those after one dose of the same vaccine in KEN SHE. METHODS: In the DoRIS trial, 930 girls aged 9-14 years in Tanzania were randomly assigned to one, two, or three doses of the 2-valent vaccine (Cervarix) or the 9-valent vaccine (Gardasil-9). The proportion seroconverting and geometric mean concentrations (GMCs) at month 24 after one dose were compared with those in women aged 15-20 years who were randomly assigned to one dose of the same vaccines at the same timepoint in KEN SHE. Batched samples were tested together by virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial:KEN SHE) was predefined as a lower bound of the 95% CI less than 0·50. FINDINGS: Month 24 HPV16 and HPV18 antibody GMCs in DoRIS were similar or higher than those in KEN SHE. 2-valent GMC ratios were 0·90 (95% CI 0·72-1·14) for HPV16 and 1·02 (0·78-1·33) for HPV18. 9-valent GMC ratios were 1·44 (95% CI 1·14-1·82) and 1·47 (1·13-1·90), respectively. Non-inferiority of antibody GMCs and seropositivity was met for HPV16 and HPV18 for both vaccines. INTERPRETATION: HPV16 and HPV18 immune responses in young girls 24 months after a single dose of 2-valent or 9-valent HPV vaccine were comparable to those in young women who were randomly assigned to a single dose of the same vaccines and in whom efficacy had been shown. A single dose of HPV vaccine, when given to girls in the target age range for vaccination, induces immune responses that could be effective against persistent HPV16 and HPV18 infection at least two years after vaccination. FUNDING: The UK Department of Health and Social Care, the Foreign, Commonwealth, & Development Office, the Global Challenges Research Fund, the UK Medical Research Council and Wellcome Trust Joint Global Health Trials scheme, the Bill and Melinda Gates Foundation, the US National Cancer Institute; the US National Institutes of Health, and the Francis and Dorothea Reed Endowed Chair in Infectious Diseases. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Therapeutic vaccination with recombinant adenovirus reduces splenic parasite burden in experimental visceral leishmaniasis.

Therapeutic vaccines, when used alone or in combination therapy with antileishmanial drugs, may have an important place in the control of a variety of forms of human leishmaniasis. Here, we describe the development of an adenovirus-based vaccine (Ad5-KH) comprising a synthetic haspb gene linked to a kmp11 gene via a viral 2A sequence. In nonvaccinated Leishmania donovani-infected BALB/c mice, HASPB- and KMP11-specific CD8(+) T cell responses were undetectable, although IgG1 and IgG2a antibodies were evident. After therapeutic vaccination, antibody responses were boosted, and IFNγ(+)CD8(+) T cell responses, particularly to HASPB, became apparent. A single vaccination with Ad5-KH inhibited splenic parasite growth by ∼66%, a level of efficacy comparable to that observed in early stage testing of clinically approved antileishmanial drugs in this model. These studies indicate the usefulness of adenoviral vectors to deliver leishmanial antigens in a potent and host protective manner to animals with existing L. donovani infection.

Unresolved issues in the management of human papillomavirus-associated mucosal high-grade pre-cancers.

This article reviews human papillomavirus-associated mucosal high-grade pre-cancers and their management. It examines pre-cancer classification systems, the natural history of HPV-associated pre-cancers, the various types of management and treatment for HPV pre-cancers, the various mucosal site-specific considerations, and then some of the unresolved issues. Different conclusions are reached for each of the relevant mucosal sites, which are cervix, vagina, vulva, anus, penis and oro-pharynx, and indeed there are differing volumes of evidence relating to each of these sites, and thus differing degrees of certainty/uncertainty in the recommendations.

EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease.

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ~600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.

LEISH2b - A phase 2b study to assess the safety, efficacy, and immunogenicity of the Leishmania vaccine ChAd63-KH in post-kala azar dermal leishmaniasis.

Background: The leishmaniases are neglected tropical diseases caused by various Leishmania parasite species transmitted by sand flies. They comprise a number of systemic and cutaneous syndromes including kala-azar (visceral leishmaniasis, VL), cutaneous leishmaniasis (CL), and post-kala-azar dermal leishmaniasis (PKDL). The leishmaniases cause significant mortality (estimated 20 - 50,000 deaths annually), morbidity, psychological sequelae, and healthcare and societal costs. Treatment modalities remain difficult. E.g., East African PKDL requires 20 days of intravenous therapy, and frequently relapsing VL is seen in the setting of HIV and immunodeficiency. We developed a new therapeutic vaccine, ChAd63-KH for VL / CL / PKDL and showed it to be safe and immunogenic in a phase 1 trial in the UK, and in a phase 2a trial in PKDL patients in Sudan.    Methods: This is a randomised double-blind placebo-controlled phase 2b trial to assess the therapeutic efficacy and safety of ChAd63-KH in patients with persistent PKDL in Sudan. 100 participants will be randomly assigned 1:1 to receive placebo or ChAd63-KH (7.5 x10 10vp i.m.) at a single time point. Follow up is for 120 days after dosing and we will compare the clinical evolution of PKDL, as well as the humoral and cellular immune responses between the two arms. Discussion: Successful development of a therapeutic vaccine for leishmaniasis would have wide-ranging direct and indirect healthcare benefits that could be realized rapidly. For PKDL patients, an effective therapeutic vaccination used alone   would have very significant clinical value, reducing the need for extensive hospitalization and chemotherapy. Combining vaccine with drug (immuno-chemotherapy) might significantly increase the effective life of new drugs, with lower dose / abbreviated regimens helping to limit the emergence of drug resistance. If therapeutic benefit of ChAd63-KH can be shown in PKDL further evaluation of the vaccine in other forms of leishmaniasis should be considered. Clinicaltrials.gov registration: NCT03969134.

Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose of HPV vaccine in historical cohorts: an immunobridging analysis of a randomised controlled trial.

BACKGROUND: Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9-14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial [CVT] and Institutional Agency for Research on Cancer [IARC] India trial). METHODS: In this immunobridging analysis of an open-label randomised controlled trial, girls were recruited from 54 government schools in Mwanza, Tanzania, into the DoRIS trial. Girls were eligible if they were aged 9-14 years, healthy, and HIV negative. Participants were randomly assigned (1:1:1:1:1:1), using permutated block sizes of 12, 18, and 24, to one, two, or three doses of the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart, Belgium) or the 9-valent vaccine (Gardasil 9, Sanofi Pasteur MSD, Lyon, France). For this immunobridging analysis, the primary objective was to compare geometric mean concentrations (GMCs) at 24 months after one dose in the per-protocol population compared with in historical cohorts: the one-dose 2-valent vaccine group in DoRIS was compared with recipients of the 2-valent vaccine Cervarix from CVT and the one-dose 9-valent vaccine group in DoRIS was compared with recipients of the 4-valent vaccine Gardasil (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) from the IARC India trial. Samples were tested together with virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial vs historical cohort) was predefined as when the lower bound of the 95% CI was greater than 0·50. This study is registered with ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility, of whom 930 were enrolled into DoRIS and 155 each were assigned to one dose, two doses, or three doses of 2-valent vaccine, or one dose, two doses, or three doses of 9-valent vaccine. 154 (99%) participants in the one-dose 2-valent vaccine group (median age 10 years [IQR 9-12]) and 152 (98%) in the one-dose 9-valent vaccine group (median age 10 years [IQR 9-12]) were vaccinated and attended the 24 month visit, and so were included in the analysis. 115 one-dose recipients from the CVT (median age 21 years [19-23]) and 139 one-dose recipients from the IARC India trial (median age 14 years [13-16]) were included in the analysis. At 24 months after vaccination, GMCs for HPV16 IgG antibodies were 22·9 international units (IU) per mL (95% CI 19·9-26·4; n=148) for the DoRIS 2-valent vaccine group versus 17·7 IU/mL (13·9-22·5; n=97) for the CVT (GMC ratio 1·30 [95% CI 1·00-1·68]) and 13·7 IU/mL (11·9-15·8; n=145) for the DoRIS 9-valent vaccine group versus 6·7 IU/mL (5·5-8·2; n=131) for the IARC India trial (GMC ratio 2·05 [1·61-2·61]). GMCs for HPV18 IgG antibodies were 9·9 IU/mL (95% CI 8·5-11·5: n=141) for the DoRIS 2-valent vaccine group versus 8·0 IU/mL (6·4-10·0; n=97) for the CVT trial (GMC ratio 1·23 [95% CI 0·95-1·60]) and 5·7 IU/mL (4·9-6·8; n=136) for the DoRIS 9-valent vaccine group versus 2·2 IU/mL (1·9-2·7; n=129) for the IARC India trial (GMC ratio 2·12 [1·59-2·83]). Non-inferiority of antibody GMCs was met for each vaccine for both HPV16 and HPV18. INTERPRETATION: One dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection. A one-dose schedule would reduce costs, simplify vaccine delivery, and expand access to the vaccine. FUNDING: UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Immunogenicity and safety of one-dose human papillomavirus vaccine compared with two or three doses in Tanzanian girls (DoRIS): an open-label, randomised, non-inferiority trial.

BACKGROUND: An estimated 15% of girls aged 9-14 years worldwide have been vaccinated against human papillomavirus (HPV) with the recommended two-dose or three-dose schedules. A one-dose HPV vaccine schedule would be simpler and cheaper to deliver. We report immunogenicity and safety results of different doses of two different HPV vaccines in Tanzanian girls. METHODS: In this open-label, randomised, phase 3, non-inferiority trial, we enrolled healthy schoolgirls aged 9-14 years from Government schools in Mwanza, Tanzania. Eligible participants were randomly assigned to receive one, two, or three doses of either the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart) or the 9-valent vaccine (Gardasil-9, Sanofi Pasteur MSD, Lyon). The primary outcome was HPV 16 specific or HPV 18 specific seropositivity following one dose compared with two or three doses of the same HPV vaccine 24 months after vaccination. Safety was assessed as solicited adverse events up to 30 days after each dose and unsolicited adverse events up to 24 months after vaccination or to last study visit. The primary outcome was done in the per-protocol population, and safety was analysed in the total vaccinated population. This study was registered in ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility. 72 girls were excluded. 930 girls were enrolled and randomly assigned to receive one dose of Cervarix (155 participants), two doses of Cervarix (155 participants), three doses of Cervarix (155 participants), one dose of Gardasil-9 (155 participants), two doses of Gardasil-9 (155 participants), or three doses of Gardasil-9 (155 participants). 922 participants received all scheduled doses within the defined window (three withdrew, one was lost to follow-up, and one died before completion; two received their 6-month doses early, and one received the wrong valent vaccine in error; all 930 participants were included in the total vaccinated cohort). Retention at 24 months was 918 (99%) of 930 participants. In the according-to-protocol cohort, at 24 months, 99% of participants who received one dose of either HPV vaccine were seropositive for HPV 16 IgG antibodies, compared with 100% of participants who received two doses, and 100% of participants who received three doses. This met the prespecified non-inferiority criteria. Anti-HPV 18 seropositivity at 24 months did not meet non-inferiority criteria for one dose compared to two doses or three doses for either vaccine, although more than 98% of girls in all groups had HPV 18 antibodies. 53 serious adverse events (SAEs) were experienced by 42 (4·5%) of 930 girls, the most common of which was hospital admission for malaria. One girl died of malaria. Number of events was similar between groups and no SAEs were considered related to vaccination. INTERPRETATION: A single dose of the 2-valent or 9-valent HPV vaccine in girls aged 9-14 years induced robust immune responses up to 24 months, suggesting that this reduced dose regimen could be suitable for prevention of HPV infection among girls in the target age group for vaccination. FUNDING: UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial.

BACKGROUND: Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa. METHODS: Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212. FINDINGS: We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86-91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8-5·4] for 0·5% PRO2000 vs 4·3 [3·6-5·2] for placebo, hazard ratio 1·05 [0·82-1·34], p=0·71), and at discontinuation (4·7 [3·8-5·8] for 2% PRO2000 gel, 3·9 [3·0-4·9] for 0·5% PRO2000 gel, and 3·9 [3·1-5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9-5·4) in the 0·5% PRO2000 group and 3·9 (3·2-4·6) in the placebo group; and was 4·5 (3·7-5·5) in the 2% PRO2000 group at discontinuation. INTERPRETATION: Although safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use. FUNDING: UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.

Vaccines against leishmaniasis: using controlled human infection models to accelerate development.

INTRODUCTION: Leishmaniasis is a neglected tropical disease that is defined by the World Health Organization as vaccine preventable. Although several new candidate vaccines are in development, no vaccine has successfully reached the market for human use. Several species of Leishmania cause human disease and have co-evolved with their respective sand fly vectors. These unique relationships have implications for initiation of infection and vaccine development. An approach to vaccine development for many infectious diseases is the use of controlled human infection models (CHIMs). AREAS COVERED: We describe the history and recent development of experimental and deliberate infection using Leishmania in humans and the rationale for developing a new sand fly-initiated CHIM to progress leishmaniasis vaccine development. Examples from other infectious diseases are discussed in the context of the development of a new leishmaniasis CHIM. We also reflect upon the manufacture of the challenge agent, practical considerations, safety, ethics, and regulatory issues. EXPERT OPINION: A new cutaneous Leishmania CHIM is being developed to enable testing of vaccines in the development pipeline. Questions remain about the use of such CHIMs to determine effectiveness of vaccines against visceral leishmaniasis. However, such a CHIM will be invaluable in expediting time to market for vaccines.

Assessing public perception of a sand fly biting study on the pathway to a controlled human infection model for cutaneous leishmaniasis.

BACKGROUND: A controlled human infection model (CHIM) involves deliberate exposure of volunteers to pathogens to assess their response to new therapies at an early stage of development. We show here how we used public involvement to help shape the design of a CHIM to support future testing of candidate vaccines for the neglected tropical disease cutaneous leishmaniasis, a disease transmitted by the bite of infected sand flies in tropical regions. METHODS: We undertook a public involvement (PI) consultation exercise to inform development of a study to test the safety and effectiveness of a sand fly biting protocol using uninfected sand flies (FLYBITE: ClinicalTrials.gov ID NCT03999970 ) and a CHIM using Leishmania major-infected sand flies (LEISH_Challenge: ClinicalTrials.gov ID NCT04512742 ), both taking place in York, UK. We involved 10 members of the public including a patient research ambassador and a previous CHIM volunteer. The session took place at The University of York, UK and examined draft study volunteer-facing material and included the CHIM study design, potential adverse events and therapeutic interventions at study endpoints. A discussion of the scientific, ethical, humanitarian and economic basis for the project was presented to the participants to provoke discourse. An inductive, thematic analysis was used to identify the participants' key concerns. RESULTS: Themes were identified relating to i) quality of volunteer-facing written information, ii) improving study design, and iii) factors to motivate involvement in the research. Group participants responded positively to the overall study aims. Initial concerns were expressed about potential risks of study involvement, but further explanation of the science and mitigations of risk secured participant support. Participants provided advice and identified improved terminology to inform the volunteer-facing material. Lastly, treatment options were discussed, and excision of any cutaneous lesion was favoured over alternatives as a treatment. CONCLUSION: The consultation exercise provided invaluable information which led to improved study design and enhanced clarity in the volunteer-facing material. The session also reinforced the need to maintain public trust in scientific rigour prior to initiation of any study. The investigators hope that this description strengthens understanding of PI in clinical research, and encourages its use within other studies.

Our research team is designing a type of research study known as a controlled human infection model (CHIM). In CHIM studies, volunteers are exposed to infections on purpose and then studied to help understand diseases. Similar experiments, where humans are infected deliberately, have been used for hundreds of years to help test treatments. CHIM studies have already been used more recently to help test vaccines for diseases such as malaria.The disease leishmaniasis, a disease affecting millions each year, is spread by the bite of an infected sand fly in tropical countries. There are currently no vaccines for leishmaniasis that are available for use in humans. It is thought that by using CHIM studies, new vaccines might be tested and then approved more quickly. Scientific researchers have had many discussions about how useful CHIM studies are, especially in terms of the science behind them, the safety of volunteers and the ethics of these studies. Researchers also understand how important it is to involve the public in designing and carrying out research, especially studies involving humans, to get an independent point-of-view. We have therefore involved the public, in some parts of designing this research, in a group discussion. We also included a person who has already taken part in a different CHIM study. These discussions have had an important effect and have changed how we plan to carry out our future research studies. We also hope that this description will encourage other researchers to include the public when planning future research.

A dose-reduction HPV vaccine immunobridging trial of two HPV vaccines among adolescent girls in Tanzania (the DoRIS trial) - Study protocol for a randomised controlled trial.

BACKGROUND: Human papillomavirus (HPV) infection is the primary cause of cervical cancer. In 2018, the World Health Organization (WHO) Director General announced his commitment to eliminate cervical cancer, with HPV vaccination as a priority. However, the costs of setting up a multi-dose HPV vaccination programme remain a barrier to its introduction. METHODS/DESIGN: We are conducting a randomised-controlled trial of reduced dose schedules of HPV vaccine in Tanzania to establish whether a single dose produces immune responses that will be effective in preventing cervical cancer. 930 girls aged 9-14 years in Mwanza, Tanzania, were randomised to one of 6 arms, comprising 3 different dose schedules of the 2-valent (Cervarix) and 9-valent (Gardasil-9) HPV vaccines: 3 doses; 2 doses given 6 months apart; or a single dose. All participants will be followed for 36 months; those in the 1 and 2 dose arms will be followed for 60 months. Trial outcomes focus on vaccine immune responses including HPV 16/18-specific antibody levels, antibody avidity, and memory B cell responses. Results will be immunobridged to historical cohorts of girls and young women in whom efficacy has been demonstrated. DISCUSSION: This is the first randomised trial of the single dose HPV vaccine schedule in the target age group. The trial will allow us to examine the quality and durability of immune responses of reduced dose schedules in a population with high burden of malaria and other infections that may affect vaccine immune responses. Initial results (24 months) are expected to be published in early 2021.

Overcoming roadblocks in the development of vaccines for leishmaniasis.

INTRODUCTION: The leishmaniases represent a group of parasitic diseases caused by infection with one of several species of Leishmania parasites. Disease presentation varies because of differences in parasite and host genetics and may be influenced by additional factors such as host nutritional status or co-infection. Studies in experimental models of Leishmania infection, vaccination of companion animals and human epidemiological data suggest that many forms of leishmaniasis could be prevented by vaccination, but no vaccines are currently available for human use. AREAS COVERED: We describe some of the existing roadblocks to the development and implementation of an effective leishmaniasis vaccine, based on a review of recent literature found on PubMed, BioRxiv and MedRxiv. In addition to discussing scientific unknowns that hinder vaccine candidate identification and selection, we explore gaps in knowledge regarding the commercial and public health value propositions underpinning vaccine development and provide a route map for future research and advocacy. EXPERT OPINION: Despite significant progress, leishmaniasis vaccine development remains hindered by significant gaps in understanding that span the vaccine development pipeline. Increased coordination and adoption of a more holistic view to vaccine development will be required to ensure more rapid progress in the years ahead.

A clinical study to optimise a sand fly biting protocol for use in a controlled human infection model of cutaneous leishmaniasis (the FLYBITE study).

Background: Leishmaniasis is a globally important yet neglected parasitic disease transmitted by phlebotomine sand flies. With new candidate vaccines in or near the clinic, a controlled human challenge model (CHIM) using natural sand fly challenge would provide a method for early evaluation of prophylactic efficacy. Methods : We evaluated the biting frequency and adverse effects resulting from exposure of human volunteers to bites of either Phlebotomus papatasi or P. duboscqi, two natural vectors of Leishmania major. 12 healthy participants were recruited (mean age 40.2 ± 11.8 years) with no history of significant travel to regions where L. major-transmitting sand flies are prevalent. Participants were assigned to either vector by 1:1 allocation and exposed to five female sand flies for 30 minutes in a custom biting chamber. Bite frequency was recorded to confirm a bloodmeal was taken. Participant responses and safety outcomes were monitored using a visual analogue scale (VAS), clinical examination, and blood biochemistry. Focus groups were subsequently conducted to explore participant acceptability. Results: All participants had at least one successful sand fly bite with none reporting any serious adverse events, with median VAS scores of 0-1/10 out to day 21 post-sand fly bite. Corresponding assessment of sand flies confirmed that for each participant at least 1/5 sand flies had successfully taken a bloodmeal (overall mean 3.67±1.03 bites per participant). There was no significant difference between P. papatasi and P. duboscqi in the number of bites resulting from 5 sand flies applied to human participants (3.3±0.81 vs 3.00±1.27 bites per participant; p=0.56) .  In the two focus groups (n=5 per group), themes relating to positive participant-reported experiences of being bitten and the overall study, were identified. Conclusions: These results validate a protocol for achieving successful sand fly bites in humans that is safe, well-tolerated and acceptable for participants. Clinicaltrials.gov registration: NCT03999970 (27/06/2019).

Characterization of a new Leishmania major strain for use in a controlled human infection model.

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical strain of Leishmania major. Two fresh strains of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

Microbicides and HIV prevention: lessons from the past, looking to the future.

PURPOSE OF REVIEW: This review provides an update on developments in HIV microbicide research in the light of recent phase 3 efficacy studies and discusses how lessons learnt from early generation microbicide candidates can assist the development of future agents. RECENT FINDINGS: Results of an interim analysis of a phase 3 trial suggested that cellulose sulfate increased the risk of HIV acquisition compared with placebo. Carraguard, SAVVY and Buffergel also failed to show any HIV protection in human efficacy trials. Recent research has focused on elucidating the reasons behind these failures as well as improving the assessment of safety and efficacy for the next generation of microbicide candidates. PRO 2000 0.5% gel is the only HIV microbicide candidate for which there are preliminary data suggesting efficacy in women. Antiretroviral agents and entry inhibitors may provide the key in the future to developing an effective HIV microbicide both for vaginal and rectal use. SUMMARY: Development of a protective 'barrier' which can be controlled by the receptive partner independent of time of coitus remains a key goal in HIV prevention. A gel or ring-delivered combination of active anti-HIV agents may prove more efficacious than a single agent alone. Challenges in evaluating and manufacturing new candidates must be overcome before a well tolerated, effective, acceptable and affordable microbicide can be produced.