Health and economic effects of introducing single-dose or two-dose human papillomavirus vaccination in India.

BACKGROUND: Cervical cancer is a major public health problem in India, where access to prevention programmes is low. The WHO-Strategic Advisory Group of Experts recently updated their recommendation for human papillomavirus (HPV) vaccination to include a single-dose option in addition to the two-dose option, which could make HPV vaccination programmes easier to implement and more affordable. METHODS: We combined projections from a type-specific HPV transmission model and a cancer progression model to assess the health and economic effects of HPV vaccination at national and state level in India. The models used national and state-specific Indian demographic, epidemiological and cost data, and single-dose vaccine efficacy and immunogenicity data from the International Agency for Research on Cancer India vaccine trial with 10-year follow-up. We compared single-dose and two-dose HPV vaccination for a range of plausible scenarios regarding single-dose vaccine protection, coverage and catch-up. We used a healthcare sector payer perspective with a time horizon of 100 years. RESULTS: Under the base-case scenario of lifelong protection of single-dose vaccination in 10-year-old girls with 90% coverage, the discounted incremental cost-effectiveness ratio (ICER) of nationwide vaccination relative to no vaccination was US$406 (₹INR30 000) per DALY (disability-adjusted life-years) averted. This lay below an opportunity-cost-based threshold of 30% Indian gross domestic product per capita in each Indian state (state-specific ICER range: US$67-US$593 per DALY averted). The ICER of two-dose vaccination versus no vaccination vaccination was US$1404 (₹INR104 000). The ICER of two-dose vaccination versus single-dose vaccination, assuming lower initial efficacy and waning of single-dose vaccination, was at least US$2282 (₹INR169 000) per DALY averted. CONCLUSIONS: Nationwide introduction of single-dose HPV vaccination at age 10 in India is highly likely to be cost-effective whereas extending the number of doses from one to two would have a less favourable profile.

Psychotherapies for the treatment of borderline personality disorder: A systematic review.

OBJECTIVE: Borderline personality disorder (BPD) is the most common personality disorder, affecting 1.8% of the general population, 10% of psychiatric outpatients, and 15%-25% of psychiatric inpatients. Practice guidelines recommend psychotherapies as first-line treatments. However, psychotherapies commonly used for the treatment of BPD are numerous, and little is known about the comparative effectiveness of each individual psychotherapy versus treatment as usual (TAU) or other psychotherapies. To systematically assess the comparative effectiveness of commonly used psychotherapies versus TAU or versus other psychotherapies for BPD treatment. METHOD: We conducted systematic literature searches in MEDLINE, EMBASE, the Cochrane Library, and APA PsycINFO up to July 14, 2022, and searched reference lists of pertinent articles and reviews. Inclusion criteria were (a) patients 13 years or older with a diagnosis of BPD, (b) treatment with commonly used psychotherapies, (c) comparison with TAU or another psychotherapy, (d) assessment of relevant BPD-related health outcomes, and (e) randomized or nonrandomized trials or controlled observational studies. Two investigators independently screened abstracts and full-text articles and graded the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: We found 25 psychotherapy studies meeting inclusion criteria with data on 2,545 participants. Seventeen studies compared nine psychotherapies with TAU and nine studies compared eight psychotherapies with another psychotherapy for the treatment of BPD. Overall, both TAU and included psychotherapies were effective in treating the severity and symptoms of BPD. Moderate certainty of evidence suggests that systems training for emotional predictability and problem solving is more effective than TAU for the treatment of BPD; low certainty of evidence suggests that dialectical behavior therapy, schema therapy, transference-focused psychotherapy, acceptance and commitment therapy, manual-assisted cognitive therapy, and cognitive behavioral therapy are more effective than TAU for treating BPD. We were unable to draw conclusions from head-to-head comparisons of psychotherapies, which were limited to single studies with very low to low certainty of evidence. CONCLUSIONS: All commonly used psychotherapies improve BPD severity, symptoms, and functioning. Our assessment found no strong evidence suggesting that any one psychotherapy is more beneficial than another. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Awareness, perceptions, and choices of physicians pertaining to human papillomavirus (HPV) vaccination in India: A formative research study.

Introduction: India accounts for one-fifth of the global burden of cervical cancer cases and mortality. A safe and effective vaccine to prevent human papillomavirus (HPV) infections, the primary cause of cervical malignancies, is available in India but multiple barriers lead to its low uptake in the country. Physicians are a key stakeholder and communicator in the Indian health system and have the potential to increase HPV vaccine uptake. Objective: We undertook formative research to understand awareness, perceptions and choices of physicians when recommending the HPV vaccine to parents of adolescent girls. Methods: We conducted in-depth interviews with 32 physicians in two districts of West Bengal. Data collection was carried out between July and August 2019. The data was transcribed, coded, and analyzed using NVivo software using the thematic analysis technique. Results: Our findings suggest that while physicians are generally aware about the burden of cervical cancer and its prevention by HPV vaccination, they face several barriers to recommending the HPV vaccine routinely and strongly. These include the lack of national-level guidance on the age eligibility and dosage, lack of practice-level opportunities such as well or non-sick visits and other routine adolescent vaccines, practice-level barriers like out-of-pocket cost and vaccine availability, and perceived parental hesitancy arising from reluctance to discuss cervical cancer, its prevention, and HPV vaccination. Conclusions: Physicians in our study exhibited hesitancy when recommending the HPV vaccine. They also faced logistical barriers. It is important that the barriers pertaining to when and how physicians recommend the vaccine be tackled through further education, policy change, and development and implementation of interventions that are evidenced-based.

Evidence-based impact projections of single-dose human papillomavirus vaccination in India: a modelling study.

BACKGROUND: Despite the high burden of cervical cancer, access to preventive measures remains low in India. A single-dose immunisation schedule could facilitate the scale-up of human papillomavirus (HPV) vaccination, contributing to global elimination of cervical cancer. We projected the effect of single-dose quadrivalent HPV vaccination in India in comparison with no vaccination or to a two-dose schedule. METHODS: In this modelling study, we adapted an HPV transmission model (EpiMetHeos) to Indian data on sexual behaviour (from the Demographic and Health Survey and the Indian National AIDS Control Organisation), HPV prevalence data (from two local surveys, from the states of Tamil Nadu and West Bengal), and cervical cancer incidence data (from Cancer Incidence in Five Continents for the period 2008-12 [volume XI], and the Indian National Centre for Disease Informatics and Research for the period 2012-16). Using the model, we projected the nationwide and state-specific effect of HPV vaccination on HPV prevalence and cervical cancer incidence, and lifetime risk of cervical cancer, for 100 years after the introduction of vaccination or in the first 50 vaccinated birth cohorts. Projections were derived under a two-dose vaccination scenario assuming life-long protection and under a single-dose vaccination scenario with protection duration assumptions derived from International Agency for Research on Cancer (IARC) India vaccine trial data, in combination with different vaccination coverages and catch-up vaccination age ranges. We used two thresholds to define cervical cancer elimination: an age-standardised incidence rate of less than 4 cases per 100 000 woman-years, and standardised lifetime risk of less than 250 cases per 100 000 women born. FINDINGS: Assuming vaccination in girls aged 10 years, with 90% coverage, and life-long protection by two-dose or single-dose schedule, HPV vaccination could reduce the prevalence of HPV16 and HPV18 infection by 97% (80% UI 96-99) in 50 years, and the lifetime risk of cervical cancer by 71-78% from 1067 cases per 100 000 women born under a no vaccination scenario to 311 (80% UI 284-339) cases per 100 000 women born in the short term and 233 (219-252) cases per 100 000 women born in the long term in vaccinated cohorts. Under this scenario, we projected that the age-standardised incidence rate threshold for elimination could be met across India (range across Indian states: 1·6 cases [80% UI 1·5-1·7] to 4·0 cases [3·8-4·4] per 100 000 woman-years), while the complementary threshold based on standardised lifetime risk was attainable in 17 (68%) of 25 states, but not nationwide (range across Indian states: 207 cases [80% UI 194-223] to 477 cases [447-514] per 100 000 women born). Under the considered assumptions of waning vaccine protection, single-dose vaccination was projected to have a 21-100% higher per-dose efficiency than two-dose vaccination. Single-dose vaccination with catch-up for girls and women aged 11-20 years was more impactful than two-dose vaccination without catch-up, with reduction of 39-65% versus 38% in lifetime risk of cervical cancer across the ten catch-up birth cohorts and the first ten routine vaccination birth cohorts. INTERPRETATION: Our evidence-based projections suggest that scaling up cervical cancer prevention through single-dose HPV vaccination could substantially reduce cervical cancer burden in India. FUNDING: The Bill & Melinda Gates Foundation.

Role of steroids in critically-ill sepsis patients: a review article and literature to review.

Sepsis, a life-threatening condition, commonly affecting critically ill patients, is a major cause of death worldwide. It is thus of great importance to determine the optimum management to cure this condition. This review article summarizes the role and effects of corticosteroids in the treatment of sepsis and septic shock, and to determine its mortality benefits. We used PubMed, Google scholar, Scopus, and Embase databases for literature review, and terminologies commonly searched were 'sepsis', 'septic shock', 'therapeutic use' and 'corticosteroids'. In this review article, we reviewed a total of eight different articles being done in last 10 years, relevant to the clinical outcome and effects of corticosteroids. Among those, two demonstrated improved clinical outcomes, two showed both improved clinical outcomes and decreased mortality, three showed increased adverse effects, and the remaining one showed unequivocal results.

Pharmacological Treatments for Borderline Personality Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Borderline personality disorder (BPD) is a debilitating psychiatric disorder that affects 0.4-3.9% of the population in Western countries. Currently, no medications have been approved by regulatory agencies for the treatment of BPD. Nevertheless, up to 96% of patients with BPD receive at least one psychotropic medication. OBJECTIVES: The objective of this systematic review was to assess the general efficacy and the comparative effectiveness of different pharmacological treatments for BPD patients. METHODS: We conducted systematic literature searches limited to English language in MEDLINE, EMBASE, the Cochrane Library, and PsycINFO up to April 6, 2021, and searched reference lists of pertinent articles and reviews. Inclusion criteria were (i) patients 13 years or older with a diagnosis of BPD, (ii) treatment with anticonvulsive medications, antidepressants, antipsychotic medications, benzodiazepines, melatonin, opioid agonists or antagonists, or sedative or hypnotic medications for at least 8 weeks, (iii) comparison with placebo or an eligible medication, (iv) assessment of health-relevant outcomes, (v) randomized or non-randomized trials or controlled observational studies. Two investigators independently screened abstracts and full-text articles and graded the certainty of evidence based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. For meta-analyses, we used restricted maximum likelihood random effects models to estimate pooled effects. RESULTS: Of 12,062 unique records, we included 21 randomized controlled trials (RCTs) with data on 1768 participants. Nineteen RCTs compared pharmacotherapies with placebo; two RCTs assessed active treatments head-to-head. Out of 87 medications in use in clinical practice, we found studies on just nine. Overall, the evidence indicates that the efficacy of pharmacotherapies for the treatment of BPD is limited. Second-generation antipsychotics, anticonvulsants, and antidepressants were not able to consistently reduce the severity of BPD. Low-certainty evidence indicates that anticonvulsants can improve specific symptoms associated with BPD such as anger, aggression, and affective lability but the evidence is mostly limited to single studies. Second-generation antipsychotics had little effect on the severity of specific BPD symptoms, but they improved general psychiatric symptoms in patients with BPD. CONCLUSIONS: Despite the common use of pharmacotherapies for patients with BPD, the available evidence does not support the efficacy of pharmacotherapies alone to reduce the severity of BPD. REGISTRATION: PROSPERO registration number, CRD42020194098.

Characteristics of Asymptomatic Bacteriuria in Diabetes Mellitus Patients: A Retrospective Observational Study.

Background and objective The term asymptomatic bacteriuria (ASB) refers to the isolation of bacteria in a urine specimen of individuals without any symptoms of urinary tract infection (UTI). Diabetes mellitus (DM) is a disease involving multiple organ systems, characterized by its chronicity and hence endless complications including ASB. This study aimed to determine the characteristics of ASB and antibiotic susceptibility patterns among patients with diabetes. Materials and methods This was a retrospective observational study conducted in a tertiary care hospital. The study included patients with a diagnosis of diabetes with no signs and symptoms of UTI but who still showed the growth of an organism in urine culture. A total of 222 urine cultures were analyzed retrospectively, ensuring that they met the inclusion criteria through non-probability consecutive sampling. Results The mean age of the study participants was 62.89 ± 13.77 years; 76% of them were females, and 61% had a family history of diabetes. The most frequent organisms isolated were Escherichia coli (E. coli), Enterococcus, Klebsiella pneumonia, Pseudomonas aeruginosa, and Enterobacter species. A total of 20 subjects had dual bacterial growth in their cultures, with Enterococcus species (n=17) being the most common organism. Gender, family history of diabetes, levels of hemoglobin A1c (HbA1c), and advanced age were all found significantly associated with ASB. Conclusion Our study is the first of its kind to analyze and examine the risk factors associated with ASB in DM patients, and to identify the pathogens involved, along with assessing their antibiotic resistance profiles.

A research agenda for non-communicable disease prevention and control in India.

BACKGROUND: Non-communicable diseases contribute to 62% of total deaths in India; of concern are the preventable premature deaths, which account for a staggering 48% of mortality. The objective of this study was to establish a consensus research agenda for non-communicable disease prevention and control that has the potential to impact polices, programmes and healthcare delivery in India. METHODS: To develop a non-communicable disease research agenda, we engaged our community collaborative board and scientific advisory group in a three-step process using two web-based surveys and one in-person meeting. First, the Delphi methodology was used to generate topics. Second, these ideas were deliberated upon during the in-person meeting, leading to the prioritisation of 23 research questions, which were subjected to Strength, Weakness, Opportunities and Threat analysis by the stakeholders using the Snow Card methodology with the scientific advisory group and community collaborative board. This step resulted in the identification of 15 low effort, high impact priority research questions for various health outcomes across research disciplines based on discussion with the larger group to reach consensus. Finally, the second web-based survey resulted in the identification of 15 key priority research questions by all stakeholders as being the most important using a linear mixed effect regression model. RESULTS: The final set of 15 priority research questions focused on interventions at the individual, community, systems and policy levels. Research questions focused on identifying interventions that strengthen healthcare systems and healthcare delivery, including models of care and improved access to non-communicable disease screening, diagnosis and treatment, determining the impact of government policies, assessing the effectiveness of prevention programmes (e.g. tobacco, environmental improvements), and testing research tools and resources to monitor non-communicable diseases at the population level. CONCLUSION: To produce the evidence base for selecting and implementing non-communicable disease programmes and policies in India, investments are needed. These investments should be guided by a national research agenda for the prevention and control of non-communicable diseases in India. Our findings could form the backbone of a national research agenda for non-communicable diseases in India that could be refined and then adopted by government agencies, the private sector, non-governmental and community-based organisations.

A systematic review of the evidence on peer education programmes for promoting the sexual and reproductive health of young people in India.

In the context of a growing adolescent population globally, it is imperative to understand which interventions will most effectively advance their sexual and reproductive health (SRH). In India and globally, peer education is often utilised as an intervention for promoting the SRH of young people. Globally, the evidence of its effectiveness is mixed. A systematic review of the literature from the Indian context gave insight into the knowledge, attitudinal, and behavioural (KAB) outcomes affected by peer education, as well as the inputs, coverage, content, and context of such interventions. Out of the over 1500 publications initially identified through the database and bibliographic searches, 13 were included in the review; no quality assessment was done, given the dearth of publications matching the inclusion criteria. Analysis of the included publications highlights the multiple ways that peer education is implemented in the Indian context, as part of multi-component programmes and as a stand-alone intervention. The KAB outcomes from these initiatives are mixed, with some multi-component and some stand-alone initiatives affecting statistically significant outcomes and others not-a finding consistent with global literature reviewed for this paper. Despite the mixed results and the limited effects of behaviour relative to knowledge, this paper proposes that peer education has a place in an overall response to improving the SRH of young people. It calls for better research on peer education in India, and for research in relation to the optimal conditions for peer education to succeed in affecting KAB and other outcomes.

Strategies to address anaemia among pregnant and lactating women in India: a formative research study.

OBJECTIVE: Over half of pregnant women in India are affected by anaemia, which can lead to premature birth, low birth weight and maternal and child mortality. Using formative research, we aimed to understand social and cultural factors around iron and folic acid (IFA) supplement provision and adherence to identify potential strategies for improving adherence and behaviours to prevent and treat anaemia among pregnant and lactating Indian women. DESIGN: In-depth interviews and focus group discussions with women and key informant interviews with health officials and workers. SETTING: Four districts in two Indian states: Allahabad and Bara Banki districts in Uttar Pradesh and Chikkballapura and Mandya districts in Karnataka. PARTICIPANTS: Pregnant and lactating women (n 65) and district officials and community health workers (n 14). RESULTS: Most women were aware of anaemia but did not understand its seriousness and consequences. All women received IFA supplements (predominantly for free), but many were not adherent because of side effects; lack of information from healthcare providers on the causes of anaemia, its seriousness and solutions and low social support. To address anaemia, women were most confident in their ability to prepare and eat healthier foods but lacked control over resources such as appropriate food availability. CONCLUSIONS: Based on the findings, we recommend multicomponent interventions to train healthcare providers, address systemic barriers and involve family members to support IFA supplement adherence and dietary changes. Future research will determine which strategies are most effective to reduce the burden of anaemia in India among pregnant and lactating women.

The relationship between oral health and COPD exacerbations.

Introduction: Poor oral health has been implicated as an independent risk factor for the development of COPD, but few studies have evaluated the association between oral health and COPD exacerbations. We aimed to determine if poor oral health is associated with COPD exacerbations and/or worse respiratory health. Methods: We performed a case-control study of oral health among COPD exacerbators and non-exacerbators. Cases (exacerbators) had experienced ≥1 exacerbation in the previous 12 months, while controls (non-exacerbators) had no exacerbations in the previous 24 months. We excluded those with <4 teeth. We evaluated the global oral health assessment, Oral Health Impact Profile (OHIP-5), dental symptoms/habits, and St. George's Respiratory Questionnaire (SGRQ). In a subset, we performed blinded dental exams to measure bleeding on probing, probing depth, clinical attachment loss, periodontitis severity, plaque index, gingival index, and carries risk. We evaluated associations between oral health and COPD exacerbations using logistic regression. Linear regression was used to assess relationships between oral health and SGRQ scores. Results: Screened non-exacerbators (n=118) were significantly more likely to have <4 teeth, compared to screened exacerbators (n=100) (44% vs 30%, respectively; p=0.046). After excluding those with <4 teeth, there were 70 cases and 66 controls. Self-reported oral health and objective dental exam measures did not vary significantly between cases vs controls. However, the odds of severe COPD exacerbations requiring hospitalizations and/or emergency department visits trended higher in those with worse dental exam compared to those with better dental exam. Worse OHIP-5 was strongly associated with worse SGRQ scores. Conclusions: Oral health status was not related to COPD exacerbations, but was associated with self-reported respiratory health. Non-exacerbators were more likely to be edentate or have ≤4 teeth compared to exacerbators. Larger studies are needed to address oral health as a potential method to improve respiratory health in patients with COPD.

Menstrual Hygiene Management and Waste Disposal in Low and Middle Income Countries-A Review of the Literature.

Menstrual hygiene management (MHM) has gained some attention and several literature reviews have been published. However, both original papers and reviews tend to focus on absorbent access and use and not on the disposal of menstrual waste. This review aims to fill a gap in the water, sanitation and hygiene (WASH) sector by bringing a focus specifically on menstrual hygiene safe disposal in low- and middle-income countries (LMIC). We reviewed published literature since 2002 on menstrual hygiene with a focus on menstrual waste management and menstrual absorbent disposal in LMIC. Database searches were conducted of both peer reviewed literature and grey literature, in addition to hand searching of references of relevant earlier literature reviews. In total 152 articles and reports were identified and 75 met the inclusion criteria and was included in the final review. Existing polices on MHM was also reviewed with a focus on India and South Africa. The review showed that disposal of menstrual waste is often neglected MHM and sanitation value chains, leading to improper disposal and negative impacts on users, the sanitation systems and the environment. Findings call for further research to gain better understandings of MHM waste streams, disposal behaviors, absorbent materials and waste management technologies to deliver health, safety, mobility and dignity for women and girls.

Intention to accept pertussis vaccine among pregnant women in Karachi, Pakistan.

BACKGROUND: Maternal immunization against pertussis is a potential strategy to protect young infants from severe disease. We assessed factors associated with intention to accept pertussis vaccination among pregnant women in Karachi, Pakistan. METHODS: We conducted a cross-sectional survey between May and August 2013 in pregnant women who visited healthcare centers in urban slums of Karachi city. Women completed a survey examining socio-demographic factors, vaccination history, knowledge on pertussis disease, perception of vaccine recommendation sources, and potential influences on vaccine decision-making. RESULTS: Of the 283 participants, 259 (92%) provided their intention to either accept or decline pertussis vaccination. Eighty-three percent women were willing to accept the pertussis vaccine if offered during pregnancy. About half (53%) of the participants had ever heard of pertussis disease. Perceptions of pertussis vaccine efficacy, safety, and disease susceptibility were strongly associated with intention to accept pertussis vaccine (p<0.01). Healthcare providers, Ministry of Health, and mass media were considered as highly reliable sources of vaccine recommendation and associated with intention to accept antenatal pertussis vaccination (p<0.001). Healthcare provider recommendation was a common reason cited by respondents for pregnant women to accept antenatal pertussis vaccination (p=0.0005). However, opinion of primary decision-makers in the family (husbands and in-laws) was a crucial reason cited by respondents for pregnant women to reject pertussis vaccination in pregnancy (p=0.003). CONCLUSION: Antenatal pertussis vaccination initiatives in South Asia should strongly consider inclusion of family members, healthcare providers, national health ministries, and mass media to help implement new vaccination programs.

Adult-onset Still's disease: current challenges and future prospects.

Adult-onset Still's disease (AOSD) - a multi-systemic inflammatory condition characterized by high fevers, polyarthritis, an evanescent rash, and pharyngitis - has been a challenging condition to diagnose expediently and treat effectively. Questions remain regarding the underlying pathophysiology and etiology of AOSD. Pathognomonic diagnostic tests and reliable biomarkers remain undiscovered. Over the past decade, important progress has been made. Diagnostic criteria employing glycosylated ferritin have improved specificity. More important, novel biologic therapies have offered important clues to AOSD's underlying pathophysiology. Cytokine-specific biologic therapies have been instrumental in providing more effective treatment for disease refractory to conventional treatment. While IL-1 therapy has demonstrated efficacy in refractory disease, novel therapies targeting IL-6 and IL-18 show great promise and are currently under investigation.

Influenza vaccine acceptance among pregnant women in urban slum areas, Karachi, Pakistan.

BACKGROUND: Facilitators and barriers to influenza vaccination among pregnant women in the developing world are poorly understood, particularly in South Asia. We assessed intention to accept influenza vaccine among ethnically diverse low-income pregnant women in Pakistan. METHODS: From May to August 2013, we conducted a cross-sectional survey of pregnant women who visited health centers in urban slums in Karachi city. We assessed intention to accept influenza vaccine against socio-demographic factors, vaccination history, vaccine recommendation sources, and other factors. RESULTS: In an unvaccinated study population of 283 respondents, 87% were willing to accept the vaccine, if offered. All except two participants were aware of symptoms typically associated with influenza. Perceived vaccine safety, efficacy, and disease susceptibility were significantly associated with intention to accept influenza vaccine (p<0.05). Regardless of intention to accept influenza vaccine, 96% rated healthcare providers as highly reliable source of vaccine information. While a recommendation from a physician was critical for influenza vaccine acceptance, parents-in-law and husbands were often considered the primary decision-makers for pregnant women seeking healthcare including vaccination. CONCLUSIONS: Maternal influenza vaccination initiatives in South Asia should strongly consider counseling of key familial decision-makers and inclusion of healthcare providers to help implement new vaccination programs.

CD40L-adjuvanted DNA/modified vaccinia virus Ankara simian immunodeficiency virus SIV239 vaccine enhances SIV-specific humoral and cellular immunity and improves protection against a heterologous SIVE660 mucosal challenge.

UNLABELLED: It remains a challenge to develop a successful human immunodeficiency virus (HIV) vaccine that is capable of preventing infection. Here, we utilized the benefits of CD40L, a costimulatory molecule that can stimulate both dendritic cells (DCs) and B cells, as an adjuvant for our simian immunodeficiency virus (SIV) DNA vaccine in rhesus macaques. We coexpressed the CD40L with our DNA/SIV vaccine such that the CD40L is anchored on the membrane of SIV virus-like particle (VLP). These CD40L containing SIV VLPs showed enhanced activation of DCs in vitro. We then tested the potential of DNA/SIV-CD40L vaccine to adjuvant the DNA prime of a DNA/modified vaccinia virus Ankara (MVA) vaccine in rhesus macaques. Our results demonstrated that the CD40L adjuvant enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV CD8 and CD4 T cell responses, significantly delayed the acquisition of heterologous mucosal SIV infection, and improved viral control. Notably, the CD40L adjuvant enhanced the control of viral replication in the gut at the site of challenge that was associated with lower mucosal CD8 immune activation, one of the strong predictors of disease progression. Collectively, our results highlight the benefits of CD40L adjuvant for enhancing antiviral humoral and cellular immunity, leading to enhanced protection against a pathogenic SIV. A single adjuvant that enhances both humoral and cellular immunity is rare and thus underlines the importance and practicality of CD40L as an adjuvant for vaccines against infectious diseases, including HIV-1. IMPORTANCE: Despite many advances in the field of AIDS research, an effective AIDS vaccine that can prevent infection remains elusive. CD40L is a key stimulator of dendritic cells and B cells and can therefore enhance T cell and antibody responses, but its overly potent nature can lead to adverse effects unless used in small doses. In order to modulate local expression of CD40L at relatively lower levels, we expressed CD40L in a membrane-bound form, along with SIV antigens, in a nucleic acid (DNA) vector. We tested the immunogenicity and efficacy of the CD40L-adjuvanted vaccine in macaques using a heterologous mucosal SIV infection. The CD40L-adjuvanted vaccine enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV T cell responses and improved protection. These results demonstrate that VLP-membrane-bound CD40L serves as a novel adjuvant for an HIV vaccine.

Epidemiology of vaccine hesitancy in the United States.

Vaccines are among the most effective public health interventions against infectious diseases. However, there is evidence in the United States for parents either delaying or refusing recommended childhood vaccination. Exemptions to school immunization laws and use of alternative schedule from those recommended by the Advisory Committee on Immunization Practices and the American Academy of Pediatrics cannot only increase the risk of children contracting vaccine-preventable diseases but also increases the risk of infecting others who are either too young to be vaccinated, cannot be vaccinated for medical reasons or did not develop a sufficient immunological response to the vaccine. Healthcare providers are cited as the most influential source by parents on vaccine decision-making. Vaccine hesitancy needs to be addressed by healthcare providers and the scientific community by listening to the parental concerns and discussing risks associated with either delaying or refusing vaccines.

Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques.

In SIV/HIV infection, the gastrointestinal tissue dominates as an important site because of the impact of massive mucosal CD4 depletion and immune activation-induced tissue pathology. Unlike AIDS-susceptible rhesus macaques, natural hosts do not progress to AIDS and resolve immune activation earlier. Here, we examine the role of dendritic cells (DCs) in mediating immune activation and disease progression. We demonstrate that plasmacytoid DCs (pDCs) in the blood up-regulate ß7-integrin and are rapidly recruited to the colorectum after a pathogenic SIV infection in rhesus macaques. These pDCs were capable of producing proinflammatory cytokines and primed a T cytotoxic 1 response in vitro. Consistent with the up-regulation of ß7-integrin on pDCs, in vivo blockade of α4ß7-integrin dampened pDC recruitment to the colorectum and resulted in reduced immune activation. The up-regulation of ß7-integrin expression on pDCs in the blood also was observed in HIV-infected humans but not in chronically SIV-infected sooty mangabeys that show low levels of immune activation. Our results uncover a new mechanism by which pDCs influence immune activation in colorectal tissue after pathogenic immunodeficiency virus infections.

Expansion of FOXP3+ CD8 T cells with suppressive potential in colorectal mucosa following a pathogenic simian immunodeficiency virus infection correlates with diminished antiviral T cell response and viral control.

FOXP3(+)CD8(+) T cells are present at low levels in humans; however, the function of these cells is not known. In this study, we demonstrate a rapid expansion of CD25(+)FOXP3(+)CD8(+) regulatory T cells (Tregs) in the blood and multiple tissues following a pathogenic SIV infection in rhesus macaques. The expansion was pronounced in lymphoid and colorectal mucosal tissues, preferential sites of virus replication. These CD8 Tregs expressed molecules associated with immune suppressor function such as CTLA-4 and CD39 and suppressed proliferation of SIV-specific T cells in vitro. They also expressed low levels of granzyme B and perforin, suggesting that these cells do not possess killing potential. Expansion of CD8 Tregs correlated directly with acute phase viremia and inversely with the magnitude of antiviral T cell response. Expansion was also observed in HIV-infected humans but not in SIV-infected sooty mangabeys with high viremia, suggesting a direct role for hyperimmune activation and an indirect role for viremia in the induction of these cells. These results suggest an important but previously unappreciated role for CD8 Tregs in suppressing antiviral immunity during immunodeficiency virus infections. These results also suggest that CD8 Tregs expand in pathogenic immunodeficiency virus infections in the nonnatural hosts and that therapeutic strategies that prevent expansion of these cells may enhance control of HIV infection.