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The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including nucleic acid (RNA and DNA) vaccines. This paper uses the BRAVATO template to review the features of a vaccine employing a proprietary mRNA vaccine platform to develop Moderna COVID-19 Vaccine (mRNA-1273); a highly effective vaccine to prevent coronavirus disease 2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In response to the pandemic the first in human studies began in March 2020 and the pivotal, placebo-controlled phase 3 efficacy study in over 30,000 adults began in July 2020. Based on demonstration of efficacy and safety at the time of interim analysis in November 2020 and at the time of trial unblinding in March 2021, the mRNA-1273 received Emergency Use Authorization in December 2020 and full FDA approval in January 2022.

Replication-deficient adenoviral vectors have been under investigation as a platform technology for vaccine development for several years and have recently been successfully deployed as an effective COVID-19 counter measure. A replication-deficient adenoviral vector based on the simian adenovirus type Y25 and named ChAdOx1 has been evaluated in several clinical trials since 2012. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) was formed to evaluate the safety and other key features of new platform technology vaccines. This manuscript reviews key features of the ChAdOx1-vectored vaccines. The simian adenovirus Y25 was chosen as a strategy to circumvent pre-existing immunity to common human adenovirus serotypes which could impair immune responses induced by adenoviral vectored vaccines. Deletion of the E1 gene renders the ChAdOx1 vector replication incompetent and further genetic engineering of the E3 and E4 genes allows for increased insertional capability and optimizes vaccine manufacturing processes. ChAdOx1 vectored vaccines can be manufactured in E1 complementing cell lines at scale and are thermostable. The first ChAdOx1 vectored vaccines approved for human use, against SARS-CoV-2, received emergency use authorization in the UK on 30th December 2020, and is now approved in more than 180 countries. Safety data were compiled from phase I-III clinical trials of ChAdOx1 vectored vaccines expressing different antigens (influenza, tuberculosis, malaria, meningococcal B, prostate cancer, MERS-CoV, Chikungunya, Zika and SARS-CoV-2), conducted by the University of Oxford, as well as post marketing surveillance data for the COVID-19 Oxford-AstraZeneca vaccine. Overall, ChAdOx1 vectored vaccines have been well tolerated. Very rarely, thrombosis with thrombocytopenia syndrome (TTS), capillary leak syndrome (CLS), immune thrombocytopenia (ITP), and Guillain-Barre syndrome (GBS) have been reported following mass administration of the COVID-19 Oxford-AstraZeneca vaccine. The benefits of thi COVID-19 vaccination have outweighed the risks of serious adverse events in most settings, especially with mitigation of risks when possible. Extensive immunogenicity clinical evaluation of ChAdOx1 vectored vaccines reveal strong, durable humoral and cellular immune responses to date; studies to refine the COVID-19 protection (e.g., via homologous/heterologous booster, fractional dose) are also underway. New prophylactic and therapeutic vaccines based on the ChAdOx1 vector are currently undergoing preclinical and clinical assessment, including vaccines against viral hemorrhagic fevers, Nipah virus, HIV, Hepatitis B, amongst others.

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including protein subunit vaccines. This article uses the BRAVATO template to review the features of the MVC-COV1901 vaccine, a recombinant protein subunit vaccine based on the stabilized pre-fusion SARS-CoV-2 spike protein S-2P, adjuvanted with CpG 1018 and aluminum hydroxide, manufactured by Medigen Vaccine Biologics Corporation in Taiwan. MVC-COV1901 vaccine is indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 12years of age and older. The template offers details on basic vaccine information, target pathogen and population, characteristics of antigen and adjuvant, preclinical data, human safety and efficacy data, and overall benefit-risk assessment. The clinical development program began in September 2020 and based on demonstration of favorable safety and immunogenicity profiles in 11 clinical trials in over 5,000 participants, it has been approved for emergency use based on immunobridging results for adults in Taiwan, Estwatini, Somaliland, and Paraguay. The main clinical trials include placebo-controlled phase 2 studies in healthy adults (CT-COV-21), adolescents (CT-COV-22), and elderly population (CT-COV-23) as well as 3 immunobridging phase 3 trials (CT-COV-31, CT-COV-32, and CT-COV-34) in which MVC-COV1901 was compared to AZD1222. There are also clinical trials studying MVC-COV1901 as homologous and heterologous boosters (CT-COV-24 and CT-COV-25). The totality of evidence based on ∼3 million vaccinees to date includes a mostly clean safety profile, with adverse events mostly being mild and self-limiting in both clinical development and post-marketing experience, proven immunogenic response, and real-world effectiveness data. The immunogenic profile demonstrates that MVC-COV1901 induces high levels of neutralizing and binding antibodies against SARS-CoV-2. There is a dose-dependent response and a significant correlation between binding and neutralizing antibody activity. Antigen-specific T-cell responses, particularly a Th1-biased immune response characterized by high levels of interferon gamma and IL-2 cytokines, have also been observed. Coupled with this, MVC-COV1901 has favorable thermostability and better safety profiles when compared to other authorized vaccines from different platforms, which make it potentially a good candidate for vaccine supply chains in global markets.

Inactivated viral vaccines have long been used in humans for diseases of global health threat (e.g., poliomyelitis and pandemic and seasonal influenza) and the technology of inactivation has more recently been used for emerging diseases such as West Nile, Chikungunya, Ross River, SARS and especially for COVID-19. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit and risk of several vaccine platform technologies, including inactivated viral vaccines. This paper uses the BRAVATO inactivated virus vaccine template to review the features of an inactivated whole chikungunya virus (CHIKV) vaccine that has been evaluated in several preclinical studies and clinical trials. The inactivated whole CHIKV vaccine was cultured on Vero cells and inactivated by ß-propiolactone.This provides an effective, flexible system for high-yield manufacturing. The inactivated whole CHIKV vaccine has favorable thermostability profiles, compatible with vaccine supply chains. Safety data are compiled in the current inactivated whole CHIKV vaccine safety database with unblinded data from the ongoing studies: 850 participants from phase II study (parts A and B) outside of India, and 600 participants from ongoing phase II study in India, and completed phase I clinical studies for 60 subjects. Overall, the inactivated whole CHIKV vaccine has been well tolerated, with no significant safety issues identified. Evaluation of the inactivated whole CHIKV vaccine is continuing, with 1410 participants vaccinated as of 20 April 2022. Extensive evaluation of immunogenicity in humans shows strong, durable humoral immune responses.

Nucleic acid (DNA and RNA) vaccines are among the most advanced vaccines for COVID-19 under development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of nucleic acid vaccines. This will facilitate the assessment by key stakeholders of potential safety issues and understanding of overall benefit-risk. The structured assessment provided by the template can also help improve communication and public acceptance of licensed nucleic acid vaccines.

Auro Vaccines LLC has developed a protein vaccine to prevent disease from Nipah and Hendra virus infection that employs a recombinant soluble Hendra glycoprotein (HeV-sG) adjuvanted with aluminum phosphate. This vaccine is currently under clinical evaluation in a Phase 1 study. The Benefit-Risk Assessment of VAccines by TechnolOgy Working Group (BRAVATO; ex-V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template may also helpcontribute to improved public acceptance and communication of licensed protein vaccines.

Beginning in December of 2019, a novel coronavirus, SARS-CoV-2, emerged in China and is now a global pandemic with extensive morbidity and mortality. With the emergence of this threat, an unprecedented effort to develop vaccines against this virus began. As vaccines are now being introduced globally, we face the prospect of millions of people being vaccinated with multiple types of vaccines many of which use new vaccine platforms. Since medical events happen without vaccines, it will be important to know at what rate events occur in the background so that when adverse events are identified one has a frame of reference with which to compare the rates of these events so as to make an initial assessment as to whether there is a potential safety concern or not. Background rates vary over time, by geography, by sex, socioeconomic status and by age group. Here we describe two key steps for post-introduction safety evaluation of COVID-19 vaccines: Defining a dynamic list of Adverse Events of Special Interest (AESI) and establishing background rates for these AESI. We use multiple examples to illustrate use of rates and caveats for their use. In addition we discuss tools available from the Brighton Collaboration that facilitate case evaluation and understanding of AESI.

Several live-attenuated viral vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of live-attenuated viral vaccines. This will help key stakeholders assess potential safety issues and understand the benefit-risk of such vaccines. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed live-attenuated viral vaccines.

Replication-incompetent adenoviral vectors have been under investigation as a platform to carry a variety of transgenes, and express various antigens as a basis for preventive or therapeutic vaccine development. A replication incompetent adenoviral vector based on human adenovirus type 26 (Ad26) has been evaluated in several clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and features of recombinant viral vector vaccines. This paper reviews the biological features of the Ad26 vectors, including tabulation of safety and risk assessment characteristics of Ad26 vector-based vaccines. Substantial information on immunogenicity, clinical safety, biological characteristics and manufacturing are reported. In the Ad26 vector, deletion of the E1 gene, rendering the vector replication incompetent and providing space for transgene insertion, is combined with additional genetic engineering for vaccine manufacturability and transgene expression optimization. These vaccines are manufactured using the E1-complementing PER.C6® cell line, a continuous, human cell-line that can be cultured in serum-free medium in a suspension to high cell densities, providing an effective and flexible system for high-yield manufacturing. Ad26 vector vaccines have favorable thermostability profiles, compatible with vaccine supply chains. Safety data are compiled in the Ad26 vaccine safety database version 4.0, with unblinded data from 23 ongoing and completed clinical studies for a total of 3912 participants in Ebola, HIV, Malaria, RSV and Filovirus Ad26-based vaccine programs. Overall, all Ad26-based vaccines have been well tolerated, with no significant safety issues identified from the available data in the current Ad26 vaccine safety database. Evaluation of Ad26-based vaccines to further characterize the safety profile is continuing, with more than 90,000 participants vaccinated as of 1st July 2020 (cut-off date). Extensive evaluation of immunogenicity in humans shows strong and durable humoral and cellular immune responses. Clinical trials have not shown meaningful impact of pre-existing immunity to Ad26 on vaccine immunogenicity, even in the presence of Ad26 neutralizing antibody titers or Ad26-targeting T cell responses at baseline. The first vaccine, against Ebola virus, that makes use of the Ad26 vector, received marketing authorization from EC on 1st July 2020, as part of the Ad26.ZEBOV, MVA BN Filo vaccine regimen. New developments based on the Ad26 vector are underway, including a COVID-19 vaccine, which is currently in clinical evaluation.

Many of the vaccines under development for COVID-19 involve the use of viral vectors. The Brighton Collaboration Benefit-Risk Assessment of Vaccines by Technology (BRAVATO, formerly the Viral Vector Vaccine Safety Working Group, V3SWG) working group has prepared a standardized template to describe the key considerations for the benefit-risk assessment of viral vector vaccines. This will facilitate key stakeholders to anticipate potential safety issues and interpret or assess safety data. This would also help improve communication and public acceptance of licensed viral vector vaccines.

Several protein vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template would also help contribute to improved public acceptance and communication of licensed protein vaccines.

BACKGROUND: To understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray. METHODS: Viral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays. RESULTS: Ad4-H5-Vtn DNA was shed from most upper respiratory tract–immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4(+) and CD8(+) T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine. CONCLUSION: Replicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets. TRIAL REGISTRATION: ClinicalTrials.gov NCT01443936 and NCT01806909. FUNDING: Intramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).

Background The single-dose live attenuated vaccine CVD 103-HgR protects against experimental Vibrio cholerae infection in cholera-naive adults for at least 6 months after vaccination. While vaccine-induced vibriocidal seroconversion is associated with protection, vibriocidal titers decline rapidly from their peak 1–2 weeks after vaccination. Although vaccine-induced memory B cells (MBCs) might mediate sustained protection in individuals without detectable circulating antibodies, it is unknown whether oral cholera vaccination induces a MBC response. Methods In a study that enrolled North American adults, we measured lipopolysaccharide (LPS)- and cholera toxin (CtxB)-specific MBC responses to PXVX0200 (derived from the CVD 103-HgR strain) and assessed stool volumes following experimental Vibrio cholerae infection. We then evaluated the association between vaccine-induced MBC responses and protection against cholera. Results There was a significant increase in % CT-specific IgG, % LPS-specific IgG, and % LPS-specific IgA MBCs which persisted 180 days after vaccination as well as a significant association between vaccine-induced increase in % LPS-specific IgA MBCs and lower post-challenge stool volume (r = −0.56, p Discussion Oral cholera vaccination induces antigen-specific MBC responses, and the anamnestic LPS-specific responses may contribute to long-term protection and provide correlates of the duration of vaccine-induced protection. Clinical trials registration: NCT01895855.

The attenuated recombinant Vibrio cholerae O1 vaccine strain CVD 103-HgR, re-developed as PXVX0200, elicits a rapid serum vibriocidal antibody (SVA) response and protects against cholera diarrhea in volunteer challenge studies. We performed a phase 3, placebo controlled, double blind, multi-center study to further assess the safety, immunogenicity, and lot-to-lot consistency of PXVX0200. Adult volunteers 18–45 years of age were randomized 8:1 to receive a single dose of 1 × 109 CFU of PXVX0200 from three production lots or saline placebo. Immunogenicity endpoints included SVA and anti-cholera toxin (CT) antibody levels on days 1, 11, 29, 91 and 181. Safety was assessed by comparing solicited signs and symptoms on days 1–8, unsolicited adverse events through day 29 and serious adverse events through day 181. A total of 3146 participants were enrolled, including 2795 vaccine and 351 placebo recipients. The SVA seroconversion rates at day 11 were 94% and 4% in the PXVX0200 and placebo recipients, respectively (P Clinical Trials Registration: Clinicaltrials.gov NCT02094586.

Cholera remains a problem in developing countries and a risk for travelers. Hypochlorhydria, blood group O, cardiac and renal disease increase the risk of developing cholera gravis. Oral vaccines containing inactivated Vibrio cholerae and requiring two doses are available in some countries. No cholera vaccine had been available for U.S. travelers for decades until 2016 when CVD 103-HgR (VAXCHORA™), an oral live attenuated vaccine, was licensed by the U.S. FDA. Areas covered: Enduring protection following wild-type cholera provided the rationale to develop a single-dose live oral vaccine. CVD 103-HgR is well-tolerated and protects against cholera caused by V. cholerae O1 of either serotype (Inaba, Ogawa) and biotype (El Tor, Classical). Since 90% vaccine efficacy is evident 10 days post-ingestion of a single dose, CVD 103-HgR can rapidly protect travelers. Vibriocidal antibody seroconversion correlates with protection;90% of U.S. adult (including elderly) vaccinees seroconvert. The U.S. Public Health Service's Advisory Committee on Immunization Practices recommends CVD 103-HgR for U.S. travelers to areas of ongoing cholera transmission. Expert commentary: Next steps include evaluations in children, post-licensure safety and effectiveness monitoring, diminishing cold chain constraints, optimizing a 'high-dose' formulation for developing countries, and diminishing/eliminating the need for water to administer a dose.

Induction of an antibody response capable of recognizing highly diverse strains is a major obstacle to the development of vaccines for viruses such as HIV and influenza. Here, we report the dynamics of B cell expansion and evolution at the single-cell level after vaccination with a replication-competent adenovirus type 4 recombinant virus expressing influenza H5 hemagglutinin. Fluorescent H1 or H5 probes were used to quantitate and isolate peripheral blood B cells and their antigen receptors. We observed increases in H5-specific antibody somatic hypermutation and potency for several months beyond the period of active viral replication that was not detectable at the serum level. Individual broad and potent antibodies could be isolated, including one stem-specific antibody that is part of a new multidonor class. These results demonstrate prolonged evolution of the B cell response for months after vaccination and should be considered in efforts to evaluate or boost vaccine-induced immunity.

The development of new approaches to cholera control relies on an accurate understanding of cholera epidemiology. However, most information on cholera incidence lacks laboratory confirmation and instead relies on surveillance systems reporting medically attended acute watery diarrhea. If recent infections could be identified using serological markers, cross-sectional serosurveys would offer an alternative approach to measuring incidence. Here, we used 1569 serologic samples from a cohort of cholera cases and their uninfected contacts in Bangladesh to train machine learning models to identify recent Vibrio cholerae O1 infections. We found that an individual’s antibody profile contains information on the timing of V. cholerae O1 infections in the previous year. Our models using six serological markers accurately identified individuals in the Bangladesh cohort infected within the last year [cross-validated area under the curve (AUC), 93.4%; 95% confidence interval (CI), 92.1 to 94.7%], with a marginal performance decrease using models based on two markers (cross-validated AUC, 91.0%; 95% CI, 89.2 to 92.7%). We validated the performance of the two-marker model on data from a cohort of North American volunteers challenged with V. cholerae O1 (AUC range, 88.4 to 98.4%). In simulated serosurveys, our models accurately estimated annual incidence in both endemic and epidemic settings, even with sample sizes as small as 500 and annual incidence as low as two infections per 1000 individuals. Cross-sectional serosurveys may be a viable approach to estimating cholera incidence.

Background. No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance. PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. Methods. Consenting healthy adult volunteers, 18–45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 108 colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. Results. The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). Conclusions. The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT01895855","term_id":"NCT01895855"}}NCT01895855

Aging is accompanied by a decline in immune function which can lead to decreased responses to vaccines. Attenuated recombinant Vibrio cholerae O1 vaccine strain CVD 103-HgR elicits a rapid serum vibriocidal antibody (SVA) response and protects against cholera diarrhea in volunteer challenge studies but has not been studied in older adults. We evaluated CVD 103-HgR (PXVX0200) in adults age 46–64, compared them to previously studied adults age 18–45, and studied age-related immunogenicity across adults 18–64 years of age. Volunteers were randomized to receive a single dose of 1 × 109 CFU of PXVX0200 or placebo. Immunogenicity endpoints included SVA and anti-cholera toxin (CT) antibody levels on days 1, 11, 29, 91 and 181 and lipopolysaccharide (LPS) and CT-specific IgA and IgG memory B cells on days 1, 91 and 181. Safety was assessed by comparing solicited signs and symptoms on days 1–8 and other adverse events through day 181. 2979 volunteers received vaccine, including 291 age 45–64. Day 11 seroconversion occurred in 90.4% of older adults vs 93.5%% of younger adults and met the endpoint of demonstrating non-inferiority between the two groups. Significant increases in LPS-specific IgG and IgA and CT-specific memory IgG memory B cells were seen at days 91 and 181. There appeared to be a continuous age-related decline in SVA seroconversion and geometric mean titers, but not memory B cell responses, across the 18–64 year age range. Most reactogenicity was mild and was more common in the placebo group. PXVX0200 appears safe and immunogenic in older adults. Clinical Trials Registration: clinicaltrials.gov NCT02100631.

HIV vaccine development is focused on designing immunogens and delivery methods that elicit protective immunity. We evaluated a combination of adenovirus (Ad) vectors expressing HIV 1086.C (clade C) envelope glycoprotein (Env), SIV Gag p55, and human pegivirus GBV-C E2 glycoprotein. We compared replicating simian (SAd7) with nonreplicating human (Ad4) adenovirus-vectored vaccines paired with recombinant proteins in a novel prime-boost regimen in rhesus macaques, with the goal of eliciting protective immunity against SHIV challenge. In both vaccine groups, plasma and buccal Env-specific IgG, tier 1 heterologous neutralizing antibodies, and antibody-dependent cell-mediated viral inhibition were readily generated. High Env-specific T cell responses elicited in all vaccinees were significantly greater than responses targeting Gag. After three intrarectal exposures to heterologous tier 1 clade C SHIV, all 10 sham-vaccinated controls were infected, whereas 4/10 SAd7- and 3/10 Ad4-vaccinated macaques remained uninfected or maintained tightly controlled plasma viremia. Time to infection was significantly delayed in SAd7-vaccinated macaques compared to the controls. Cell-associated and plasma virus levels were significantly lower in each group of vaccinated macaques compared to controls; the lowest plasma viral burden was found in animals vaccinated with the SAd7 vectors, suggesting superior immunity conferred by the replicating simian vectors. Furthermore, higher V1V2-specific binding antibody titers correlated with viral control in the SAd7 vaccine group. Thus, recombinant Ad plus protein vaccines generated humoral and cellular immunity that was effective in either protecting from SHIV acquisition or significantly reducing viremia in animals that became infected, consequently supporting additional development of replicating Ad vectors as HIV vaccines. IMPORTANCE There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV infection and limits in vivo viral replication and associated pathogenesis. Although replicating virus vectors have been advanced as HIV vaccine platforms, there have not been any direct comparisons of the replicating to the nonreplicating format. The present study directly compared the replicating SAd7 to nonreplicating Ad4 vectors in macaques and demonstrated that in the SAd7 vaccine group, the time to infection was significantly delayed compared to the control group, and V1V2 Env-specific binding antibodies correlated with viral outcomes. Viral control was significantly enhanced in vaccinated macaques compared to controls, and in infected SAd7-vaccinated macaques compared to Ad4-vaccinated macaques, suggesting that this vector may have conferred more effective immunity. Because blocking infection is so difficult with current vaccines, development of a vaccine that can limit viremia if infection occurs would be valuable. These data support further development of replicating adenovirus vectors.

Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 × 10 8 CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 × 10 9 CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 × 10 8 -CFU standard dose ( n = 50) or a ≥2 × 10 9 -CFU high dose ( n = 50) of PaxVax CVD 103-HgR with buffer or two doses ( n = 50) of Shanchol inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR ( P = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, P = 0.045) and was ∼2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose ( P > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.)

Immunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible. In a recent cholera challenge trial (W. H. Chen et al., Clin Infect Dis 62:1329–1335, 2016, https://doi.org/10.1093/cid/ciw145 ), 134 North American cholera-naive volunteers were randomized to receive either the live, attenuated single-dose cholera vaccine CVD (Center for Vaccine Development) 103-HgR or placebo, and the titers of vibriocidal antibodies against the classical Inaba strain were assessed at 10 days after treatment. Subsequent to the immunologic evaluation, each subject ingested a fixed quantity of virulent Vibrio cholerae O1 El Tor Inaba. Data from this trial suggest that the vaccine-induced increase in the vibriocidal antibody titer prior to challenge is tightly linked with protection: 51/51 vaccinees with postvaccination vibriocidal antibody titers of ≥2,560 were protected against moderate/severe diarrhea, and 60/62 vaccinees who seroconverted or experienced a 4-fold or greater increase in vibriocidal antibody titer relative to prevaccination levels were similarly protected. Atypically high vibriocidal antibody titers were observed in some placebo subjects; protection was limited in these individuals and differed substantially from the level of protection experienced by vaccinees with the same postvaccination titers. Since only 1 of 66 placebo recipients experienced seroconversion, seroconversion was found to be uniquely associated with vaccination and insensitive to the effects of factors that can cause titers to be elevated but are weakly associated with protection. Thus, vibriocidal antibody seroconversion was found to be better than the vibriocidal antibody titer for inferring vaccine efficacy in cholera-naive populations for which studies based upon exposure to V. cholerae are impractical. (This study has been registered at ClinicalTrials.gov under registration no. NCT01895855.)

One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera vaccine CVD 103-HgR (Vaxchora) results in antibody responses to the in vivo -induced toxin-coregulated pilus antigen TcpA, we measured IgA and IgG responses to Vibrio cholerae O1 El Tor TcpA in a subset of participants in a recently reported experimental challenge study. Participants were challenged with V. cholerae O1 El Tor Inaba N16961 either 10 days or 90 days after receiving the vaccine or a placebo. Neither vaccination nor experimental infection with V. cholerae alone resulted in a robust TcpA IgG or IgA response, but each did elicit a strong response to cholera toxin. However, compared to placebo recipients, vaccinees had a marked increase in IgG TcpA antibodies following the 90-day challenge, suggesting that vaccination with CVD 103-HgR resulted in priming for a subsequent response to TcpA. No such difference between vaccine and placebo recipients was observed for volunteers challenged 10 days after vaccination, indicating that this was insufficient time for vaccine-induced priming of the TcpA response. The priming of the response to TcpA and potentially other antigens expressed in vivo by attenuated V. cholerae may have relevance to the maintenance of immunity in areas where cholera is endemic.

OBJECTIVE Young men who have sex with men (MSM) and MSM of color have the highest HIV incidence in the United States. To explore possible explanations for these disparities and known individual risk factors, we analyzed the per contact risk (PCR) of HIV seroconversion in the early highly active antiretroviral therapy era. METHODS Data from 3 longitudinal studies of MSM (HIV Network for Prevention Trials Vaccine Preparedness Study, EXPLORE behavioral efficacy trial, and VAX004 vaccine efficacy trial) were pooled. The analysis included visits where participants reported unprotected receptive anal intercourse (URA), protected receptive anal intercourse, or unprotected insertive anal intercourse (UIA) with an HIV seropositive, unknown HIV serostatus, or an HIV seronegative partner. We used regression standardization to estimate average PCRs for each type of contact, with bootstrap confidence intervals. RESULTS The estimated PCR was highest for URA with an HIV seropositive partner (0.73%; 95% bootstrap confidence interval [BCI]: 0.45% to 0.98%) followed by URA with a partner of unknown HIV serostatus (0.49%; 95% BCI: 0.32% to 0.62%). The estimated PCR for protected receptive anal intercourse and UIA with an HIV seropositive partner was 0.08% (95% BCI: 0.0% to 0.19%) and 0.22% (95% BCI: 0.05% to 0.39%), respectively. Average PCRs for URA and UIA with HIV seropositive partners were higher by 0.14%-0.34% among younger participants and higher by 0.08% for UIA among Latino participants compared with white participants. Estimated PCRs increased with the increasing number of sexual partners, use of methamphetamines or poppers, and history of sexually transmitted infection. CONCLUSIONS Susceptibility or partner factors may explain the higher HIV conversion risk for younger MSM, some MSM of color, and those reporting individual risk factors.

Background Antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae may protect against cholera; however, little is known about this immune response in infected immunologically naïve humans. Methodology We measured serum anti-OSP antibodies in adult North American volunteers experimentally infected with V. cholerae O1 Inaba El Tor N16961. We also measured vibriocidal and anti-cholera toxin B subunit (CtxB) antibodies and compared responses to those in matched cholera patients in Dhaka, Bangladesh, an area endemic for cholera. Principal findings We found prominent anti-OSP antibody responses following initial cholera infection: these responses were largely IgM and IgA, and highest to infecting serotype with significant cross-serotype reactivity. The anti-OSP responses peaked 10 days after infection and remained elevated over baseline for ≥ 6 months, correlated with vibriocidal responses, and may have been blunted in blood group O individuals (IgA anti-OSP). We found significant differences in immune responses between naïve and endemic zone cohorts, presumably reflecting previous exposure in the latter. Conclusions Our results define immune responses to O-specific polysaccharide in immunologically naive humans with cholera, find that they are largely IgM and IgA, may be blunted in blood group O individuals, and differ in a number of significant ways from responses in previously humans. These differences may explain in part varying degrees of protective efficacy afforded by cholera vaccination between these two populations. Trial registration number ClinicalTrials.gov NCT01895855., Author summary Cholera is an acute, secretory diarrheal disease caused by Vibrio cholerae O1. There is a growing body of evidence that immune responses targetting the O-specific polysaccharide (OSP) of V. cholerae are associated with protecton against cholera. Despite this, little is known about immune responses targeting OSP in immunologically naive individals. Cholera affects populations in severely resource-limited areas. To address this, we assessed anti-OSP immune responses in North American volunteers experimentally infected with wild type V. cholerae O1 El Tor Inaba strain N16961. We found that antibody responses were largely IgM and IgA, cross-reacted to both Inaba and Ogawa serotypes, and correlated with vibriocidal responses. We found no association of responses to severity of disease, but did find that blood group O individuals mounted lower IgA fold-changes to OSP than did non-blood group O individuals. Individuals with blood group O are at particular risk for severe cholera, and are less well protected against cholera following oral vaccination. We also compared anti-OSP responses in previously unexposed individuals to responses in matched endemic zone patients, and found a number of significant differences. Such differences may explain in part the varying degrees of protective efficacy afforded by cholera vaccination between these two populations.

Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed.

Currently, no cholera vaccine is available for persons traveling from the United States to areas of high cholera transmission and who for reasons of occupation or host factors are at increased risk for development of the disease. A single-dose oral cholera vaccine with a rapid onset of protection would be particularly useful for such travelers and might also be an adjunct control measure for cholera outbreaks. The attenuatedVibrio choleraeO1 vaccine strain CVD 103-HgR harbors a 94% deletion of the cholera toxin A subunit gene (ctxA) and has a mercury resistance gene inserted in the gene encoding hemolysin A. We undertook a phase I randomized placebo-controlled two-site trial to assess the safety and immunogenicity of a preliminary formulation of CVD 103-HgR prepared from new master and working cell banks. Healthy young adults were randomized (5:1 vaccinees to placebo recipients) to receive a single oral dose of ∼4.4 × 108CFU of vaccine or a placebo. Blood serum vibriocidal and cholera toxin-specific IgG antibodies were measured before and 10, 14, and 28 days following vaccination or placebo. Excretion of the vaccine strain in the stool was assessed during the first week postvaccination. A total of 66 subjects were enrolled, comprising 55 vaccinees and 11 placebo recipients. The vaccine was well tolerated. The overall vibriocidal and anti-cholera toxin seroconversion rates were 89% and 57%, respectively. CVD 103-HgR is undergoing renewed manufacture for licensure in the United States under the auspices of PaxVax. Our data mimic those from previous commercial formulations that elicited vibriocidal antibody seroconversion (a correlate of protection) in ∼90% of vaccinees. (This study has been registered at ClinicalTrials.gov under registration no. NCT01585181.)

Summary Background Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus. Methods We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18–40 years to receive one of five doses of Ad4-H5-Vtn (10 7 viral particles [VP], 10 8 VP, 10 9 VP, 10 10 VP, 10 11 VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 μg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798. Findings We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6–17) and three of 41 placebo recipients (7%, 2–20) seroconverted. HAI GMT was 6 (95% CI 5–7) for vaccinees, and 5 (5–6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 10 11 VP cohort (100%; 95% CI 82–100) and eight of 22 placebo recipients (36%; 17–59); 17 of 19 participants in the 10 11 VP cohort (89%; 67–99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5–40); GMT was 135 (89–205) with 10 11 VP, compared with 13 (7–21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16·8%] of 125 vs one [2·4%] of 41, p=0·017; 24 [19·2%] of 125 vs two [4·9%] of 41, p=0·027; 41 [32·8%] of 125 vs six [14·6%] of 41, p=0·028; respectively). No serious treatment-related adverse events occurred. Interpretation Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1. Funding Wellcome Trust Foundation, PaxVax.

In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration. To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains.

Background HIV spread rapidly amongst injecting drug users (IDUs) in Bangkok in the late 1980s. In recent years, changes in the drugs injected by IDUs have been observed. We examined data from an HIV vaccine trial conducted amongst IDUs in Bangkok during 1999–2003 to describe drug injection practices, drugs injected, and determine if drug use choices altered the risk of incident HIV infection. Methods The AIDSVAX B/E HIV vaccine trial was a randomized, double-blind, placebo-controlled trial. At enrolment and every 6 months thereafter, HIV status and risk behaviour were assessed. A proportional hazards model was used to evaluate demographic characteristics, incarceration, drug injection practices, sexual activity, and drugs injected during follow-up as independent predictors of HIV infection. Results The proportion of participants injecting drugs, sharing needles, and injecting daily declined from baseline to month 36. Amongst participants who injected, the proportion injecting heroin declined (98.6–91.9%), whilst the proportions injecting methamphetamine (16.2–19.6%) and midazolam (9.9–31.9%) increased. HIV incidence was highest amongst participants injecting methamphetamine, 7.1 (95% CI, 5.4–9.2) per 100 person years. Injecting heroin and injecting methamphetamine were independently associated with incident HIV infection. Conclusions Amongst AIDSVAX B/E vaccine trial participants who injected drugs during follow-up, the proportion injecting heroin declined whilst the proportion injecting methamphetamine, midazolam, or combinations of these drugs increased. Controlling for heroin use and other risk factors, participants injecting methamphetamine were more likely to become HIV-infected than participants not injecting methamphetamine. Additional HIV prevention tools are urgently needed including tools that address methamphetamine use.

Background Cholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera. Methodology We assessed adult North American volunteers (n = 46) who were vaccinated with 5 × 108 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination. Principal findings Vaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume (r = −0.44, P = 0.002; r = −0.36, P = 0.01; respectively), and none of 27 vaccinees who developed a ≥1.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01). Conclusion Oral vaccination with live attenuated cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these anti-OSP responses correlate with protection against diarrhea following experimental challenge with V. cholerae O1. Trial registration ClinicalTrials.gov NCT01895855, Author summary Cholera is a severe watery diarrheal disease, caused by pathogenic strains of V. cholerae. Protective immunity against cholera is serogroup specific, and serogroup specificity is determined by the O-specific polysaccharide (OSP) of V. cholerae lipopolysaccharide (LPS). Despite this, no previous work has directly assessed correlation of OSP-immune responses and protection against cholera. In this study, we assessed adult North American volunteer’s antibody responses targeting OSP after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and we assessed correlation of protection against cholera with such antibody responses. Oral vaccination was associated with the induction of significant IgM and IgA responses against OSP, and these responses correlated with vibriocidal responses. There was significant negative correlation of OSP responses and post-challenge stool volume, and none of the volunteers who developed an anti-OSP antibody responses of any isotype of ≥1.5 fold developed moderate or severe cholera following experimental challenge. In summary, vaccination with live attenuated oral cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these responses highly correlate with protection against cholera.

We investigated effects of vaccination with AIDSVAX B/E HIV-1 candidate vaccine on blood and seminal plasma HIV-1 RNA viral loads (BVL and SVL, respectively) in vaccine recipients (VRs) and placebo recipients (PRs) who acquired infection.Linear mixed models were fitted for repeated measurements of BVL. Generalized estimating equations were used to assess the difference in SVL detectability between VRs and PRs.A total of 196 participants became HIV-1 infected during the trial. Thirty-two (16%) became infected with HIV-1 subtype B and 164 (84%) with HIV-1 subtype CRF01_AE. Per protocol-specified analysis, there were no differences in BVL levels between VRs and PRs. When stratified by HIV-1-infecting subtype, vaccination with AIDSVAX B/E was initially associated with higher BVL among HIV-1 CRF01_AE-infected VRs compared with HIV-1 CRF01_AE-infected PRs; however, this difference did not persist over time. HIV-1 subtype B-infected VRs had slightly higher BVL levels and were more likely to have detectable SVL during the follow-up period than HIV-1 subtype B-infected PRs.Subtle differences in BVL and SVL were detected between VRs and PRs. These results may help to further understand the dynamics between HIV-1 vaccination, HIV-1-infecting subtypes, and subsequent viral expression in different body compartments.

This study investigated gp120-binding antibody and neutralizing activity at the gingival- and cervical-mucosal levels in response to a bivalent gp120 candidate vaccine. Women who met the studys inclusion criteria for documented high-risk behaviors participated in a nested substudy of the multicenter phase 3 trial of human immunodeficiency virus (HIV)-vaccine efficacy VAX004. Gingival cervicovaginal lavage and plasma specimens were collected at 6-month intervals for 3 years. Bindingantibody and neutralizing-activity assays quantified the presence of anti-HIV activity in mucosal specimens. Vaccine recipients were more likely than placebo recipients to have IgG binding antibodies in all 3 compartments tested and to have only IgA binding antibody in plasma (P < .0001).The relationship between vaccine and cervicovaginal IgG achieved significance (odds ratio [OR] 6.6 [P = .01]) but was weakened by the presence of cervicovaginal leukocytes. There was no relationship between immunization and the presence of neutralizing activity in either bivariate or multivariate modeling (OR 6.0 [P = .29]). Vaccination is associated with the presence of both gp120-binding IgG in all compartments and plasma IgA but not with neutralizing activity. There is a role for the measurement of mucosal immunity in response to candidate vaccines and in particular for a determination of HIV-specific neutralizing antibodies. (authors)

The HIV epidemic among injecting drug users (IDUs) in Bangkok was initially dominated by HIV subtype B and later by the recombinant CRF01_AE. The present study investigates the distribution of the 2 variants in time and how it is affected by changes in injecting risk behavior and treatment. A mathematic model describing the spread of HIV subtype B and CRF01_AE among IDUs was developed and data from the AIDSVAX B/E cohort of IDUs in Bangkok were used. From the model it was calculated that during 1999 to 2003 the annual incidence of HIV was around 0.6 and 2.7 to 3.9 infections per 100 person-years for subtype B and CRF01_AE respectively. Of the new infections 18% and 72% are first infections with subtype B and CRF01_AE respectively and 9% are super-infections. With increases in risk behavior the fraction of super-infections rises. If treatment reduces the infectivity of CRF01_AE more than that of subtype B the fraction of subtype B infections should increase. Subtype B should remain prevalent in a small but considerable fraction of the population for a long time. Changes in risk behavior and the introduction of treatment may alter the distribution of subtypes but CRF01_AE should remain dominant. (authors)

Recent outbreaks of syphilis and gonorrhea coupled with reported increases in HIV-risk behavior among men who have sex with men (MSM) have raised concerns about a potential resurgence of HIV among MSM. These concerns have led some to suggest the need for a paradigm shift in how HIV-prevention programs are designed and implemented. In this analysis, baseline demographic, sexual partnership, and substance use information was used to identify contextual-risk groups among 5,095 HIV-seronegative MSM enrolled in a 36-month phase 3 HIV vaccine efficacy trial across 61 sites primarily in North America. Eight demographic and behavioral contextual risk groups were identified, with annualized HIV seroincidence ranging from 1.8% to 6.3% across groups. Men in primary HIV-serodiscordant relationships had the lowest HIV seroincidence (1.8%), while an older group of men with many sex partners had the highest (6.3%). Visit-schedule compliance and study retention were lowest among younger non-White men and highest among older popper users, with annualized HIV seroincidence of 2.9% and 3.5%, respectively. Differences in HIV incidence, study compliance, and retention observed among contextual-risk groups suggest that responsiveness to heterogeneity within risk group (eg, MSM) could benefit screening, enrollment, and retention of HIV-prevention programs and intervention trials, reducing the time and cost related to their design, implementation, and conclusion.

The BED capture enzyme immunoassay (BED CEIA) for recent infection was developed for the estimation of HIV-1 incidence in a population from a single cross-sectional survey. To evaluate performance, we applied the assay to specimen sets obtained from a longitudinal cohort study, the AIDSVAX B/B vaccine trial, in which there was an independent and conventional measure of observed incidence. The BED CEIA was performed on specimens obtained during follow-up for seroconversion conducted every 6 months for 3 years. There was excellent agreement between the observed and BED-estimated incidence for all the intervals. The cumulative, annualized incidence observed in the cohort was 3.10 new infections per 100 person-years (95% CI, 2.57-3.63). The corresponding BED-estimated incidence was 2.91 (2.30-3.53). We also estimated the effect of varied prevalence on a fixed incidence. Because some specimens from persons with longer-term infection are classified as recent by the assay, this can inflate the incidence estimate. We quantify this effect and discuss potential mitigation by excluding certain specimens on clinical grounds, by relying on trend differences rather than absolute incidence estimates, by secondary confirmatory testing, or by analytic adjustments for misclassification. Cross-sectional HIV incidence estimation circumvents many of the drawbacks associated with longitudinal cohort studies, but there are test-specific limitations that should be considered in the design of population surveys.

Objective: Breast milk transmission continues to account for a large proportion of cases of mother-to-child transmission of HIV-1 worldwide. An effective HIV-1 vaccine coupled with either passive immunization or short-term antiretroviral prophylaxis represents a potential strategy to prevent breast milk transmission. This study evaluated the safety and immunogenicity of ALVAC HIV-1 vaccine with and without a subunit envelope boost in infants born to HIV-1-infected women. Design: Placebo-controlled, double-blinded study. Methods: Infants born to HIV-1-infected mothers in the US were immunized with a prime-boost regimen using a canarypox virus HIV-1 vaccine (vCP1452) and a recombinant glycoprotein subunit vaccine (rgp120). Infants (n = 30) were randomized to receive: vCP1452 alone, vCP1452 + rgp120, or corresponding placebos. Results: Local reactions were mild or moderate and no significant systemic toxicities occurred. Subjects receiving both vaccines had gp120-specific binding serum antibodies that were distinguishable from maternal antibody. Repeated gp160-specific lymphoproliferative responses were observed in 75%. Neutralizing activity to HIV-1 homologous to the vaccine strain was observed in 50% of the vCP1452 + rgp120 subjects who had lost maternal antibody by week 24. In some infants HIV-1-specific proliferative and antibody responses persisted until week 104. HIV-1 -specific cytotoxic T lymphocyte responses were detected in two subjects in each treatment group; the frequency of HIV-1 specific cytotoxic T lymphocyte responses did not differ between vaccine and placebo recipients. Conclusion: The demonstration of vaccine-induced immune responses in early infancy supports further study of HIV-1 vaccination as a strategy to reduce breast milk transmission.

The possible reemergence of smallpox through bioterrorism requires the preparation of adequate stockpiles of vaccine. Dryvax, the only US-licensed vaccinia virus smallpox vaccine, has an unacceptable safety profile in the pre-event setting. LC16m8 is a Japanese-licensed attenuated vaccinia virus strain that has been safely used in over 50,000 persons. Until now, efficacy of this vaccine was unproven. Using two animal models, we show that LC16m8 and Dryvax elicit comparable humoral immune responses after a single vaccination and equivalently protect against lethal poxvirus disease. Thus, LC16m8 shows promise as a safe and effective smallpox vaccine with the potential for replacing Dryvax.

The frequency of moderate to severe adverse reactions associated with smallpox vaccines currently stockpiled in the US, and the continued threat of bioterrorism have prompted the development of effective vaccines with improved safety profiles. LC16m8, an attenuated, replicating smallpox vaccine derived from the Lister strain of vaccinia, is currently licensed in Japan where it was safely used in over 50,000 children in the 1970s. It has been shown to have markedly less neurotoxicity than unattenuated vaccines in nonclinical studies. LC16m8 is immunogenic after a single dose, and recent studies in two different animal models have demonstrated protective efficacy equivalent to that of the only FDA-licensed smallpox vaccine. This article reviews the history and available scientific literature regarding LC16m8 and provides comparisons to other smallpox vaccines.

Understanding why people join HIV vaccine efficacy trials is critical for trial recruitment and education efforts. We assessed participants' motivations for joining the VaxGen VAX004 study, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial. Of 5417 participants, 94% were men who have sex with men (MSM) and 6% were women at risk for heterosexual transmission of HIV. Most participants gave altruistic reasons for trial participation: 99% reported having joined to help find an HIV vaccine, and 98% reported having joined to help their community. Some gave more personal reasons: 56% joined to reduce risk behavior and 46% joined to get protection from HIV Additional reasons related to receiving services or compensation included to obtain information about HIV (75%), to receive free HIV testing (34%), and for financial reimbursement (14%). Multivariate logistic regression analysis showed that female participants were significantly more motivated than male participants to join the trial for protection and to receive services or compensation (all P < 0.05). Participants with 13 or more sex partners in the 6 months before enrollment were more likely than those with fewer sex partners to report having joined the trial for protection but less likely to have joined to reduce risk behavior (both P < 0.05). Because many participants reported personal protection from HIV as their reason for joining, vaccine trial risk-reduction counseling should continue to emphasize the placebo-controlled trial design and unknown efficacy of the test product, particularly for women and persons with large numbers of sex partners. Because a significant minority of participants reported joining to receive HIV information, HIV testing, and financial reimbursement, a need is indicated for provision of HIV prevention services outside research trials and for monitoring to ensure that participants are not motivated to join trials for financial gain.

Background. An objective of the first efficacy trial of a candidate vaccine containing recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein 120 (rgp120) antigens was to assess correlations between antibody responses to rgp120 and the incidence of HIV-1 infection. Methods. Within the randomized trial (for vaccinees, n = 3598; for placebo recipients, n = 1805), binding and neutralizing antibody responses to rgp120 were quantitated. A case-cohort design was used to study correlations between antibody levels and HIV-1 incidence. Results. Peak antibody levels were significantly inversely correlated with HIV-1 incidence. The relative risk (RR) of infection was 0.63 (95% confidence interval, 0.45-0.89) per log10 higher neutralization titer against HIV-1MN, and the RRs of infection for second-, third-, and fourth-quartile responses of antibody blocking of gp120 binding to soluble CD4 versus first-quartile responses (the lowest responses) were 0.35, 0.28, and 0.22, respectively. Conclusions. Despite inducing a complex, robust immune response, the vaccine was unable to reduce the incidence of HIV-1. Two interpretations of the correlative results are that the levels of antibodies (i) caused both an increased (low responders) and decreased (high responders) risk of HIV-1 acquisition or (ii) represented a correlate of susceptibility to HIV-1 but had no causal effect on susceptibility. Although the data cannot definitively discriminate between these 2 explanations, (ii) appears to be more likely.

We report a randomized, double-blind, multicenter trial in which amphotericin B colloidal dispersion (ABCD [Amphotec]; 6 mg/kg/day) was compared with amphotericin B (AmB; 1.0-1.5 mg/kg/day) for the treatment of invasive aspergillosis in 174 patients. For evaluable patients in the ABCD and AmB treatment groups, respective rates of therapeutic response (52% vs. 51%; P=1.0), mortality (36% vs. 45%; P=.4), and death due to fungal infection (32% vs. 26%; P=.7) were similar. Renal toxicity was lower (25% vs. 49%; P=.002) and the median time to onset of nephrotoxicity was longer (301 vs. 22 days; P

OA16.01 Background: Induction of durable antibody responses capable of neutralizing diverse HIV-1 isolates is the most important goal in HIV vaccinology. Broad and potent HIV Env-specific antibodies isolated from humans are characterized by binding to conserved sites on Env and by high levels of hypermutation. Live virus recombinant vectors may provide prolonged exposure to transgene-encoded antigen and may more potently drive affinity maturation than non-replicating vectors. We report results of a small Phase 1 trial of mucosal immunization with live adenovirus type 4 encoding influenza H5 HA (Ad4-H5-Vtn) as a model antigen. We explored its ability to induce durable, broad neutralizing antibody responses through upper respiratory tract application. Methods: Live Ad4-H5Vtn (103-108 viral particles (VP)) was administered by tonsillar swab or by nasal spray in a dose escalation study. Controls received (1010 VP) as enteric-coated capsules. Neutralizing antibodies were measured by a pseudotype HA lentiviral vector system. B cells were isolated using fluorescent HA probes. Immunoglobulin genes were cloned for mutation analysis, and re-expressed to measure neutralization potency and breadth. Results: The vaccine was well tolerated and symptoms were consistent with mild URI. Tonsillar and nasal immunizations were the most immunogenic routes inducing neutralizing antibody responses at day 60 (ID50=809 and 666 respectively) which rose during the first 6 months. B cells that expanded early were specific for both H1 and H5 and were directed to the conserved stalk, with H5 HA-monospecific cells expanding by 6 months. The median level of hypermutation was 3.6% compared to germline at week 4 and 7.4% at weeks 34–52. However, some antibodies contained 13–34% mutation and neutralized group 1 and 2 viruses. Conclusions: A single dose of live recombinant Ad4-H5 can induce highly mutated antibodies, suggesting that mucosal administration is a promising platform for the induction of HIV-specific neutralizing antibodies.