Prototype Pathogens for Vaccine and Monoclonal Antibody Countermeasure Development: NIAID Workshop Process and Outcomes for Viral Families of Pandemic Potential.

Given the increased risk of pandemics driven by emerging and reemerging infectious diseases, it is imperative that the United States and global scientific community be better prepared for future threats by prioritizing and launching key research programs and strategies. In December 2021, the National Institute of Allergy and Infectious Diseases (NIAID) published its pandemic preparedness plan, which focuses on the prototype pathogen approach for medical countermeasure development. The plan was introduced before its release at a NIAID-hosted workshop in November 2021 that featured scientific experts from the extramural community, government, and the private sector and focused on selection of prototype pathogens from 10 viral families with pandemic risk and moderate resources. This article will serve as an introduction to this special issue and will briefly define the prototype pathogen approach, describe the workshop goals and process for outcomes, and provide an outline of the viral working group articles to follow and future directions for NIAID.

Prototype Pathogen Approach for Vaccine and Monoclonal Antibody Development: A Critical Component of the NIAID Plan for Pandemic Preparedness.

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) emerged 20 years ago, presaging a series of subsequent infectious disease epidemics of international concern. The recent emergence of SARS-CoV-2 has underscored the importance of targeted preparedness research to enable rapid countermeasure development during a crisis. In December 2021 the National Institute of Allergy and Infectious Diseases (NIAID), building upon the successful strategies developed during the SARS-CoV-2 response and to prepare for future pandemics, published a pandemic preparedness plan that outlined a research strategy focused on priority pathogens, technology platforms, and prototype pathogens. To accelerate the discovery, development, and evaluation of medical countermeasures against new or previously unknown pathogens of pandemic potential, we present here a strategy of research directed at select prototype pathogens. In this manner, leveraging a prototype pathogen approach may serve as a powerful cornerstone in biomedical research preparedness to protect public health from newly emerging and reemerging infectious diseases.

Active video games and weight management in overweight children and adolescents-systematic review and meta-analysis.

BACKGROUND: The prevalence of childhood obesity has been increasing for several decades. Active video games (AVG) may be an effective intervention to help manage this rising health crisis. The aim of this review is to evaluate whether AVG are effective at reducing weight or improving body composition in overweight youths. METHOD: Medline, Embase, SportDiscus, ASSIA, CINAHL Plus, CENTRAL, CDSR and PsychINFO databases were searched for studies assessing quantitative or qualitative impact of AVG in overweight adolescents published in English. Three authors screened the results using inclusion/exclusion criteria. RESULTS: A total of 12 studies met the inclusion criteria; 11 reported a significant decrease in at least one weight outcome. Results from seven randomized controlled trials were pooled by meta-analysis, which compared with controls subjects in AVG groups demonstrated greater body mass index (BMI) Z-score reduction (mean difference: -0.09 (-0.12, -0.05) I2 = 34%, P < 0.0001). The mean weight reduction (-2.66 Kg (-5.67, +0.35) I2 = 0%, P = 0.08) and BMI (-2.29 (-4.81, +0.22) I2 = 49%, P = 0.07) were greater in AVG groups but results did not reach statistical significance. CONCLUSIONS: BMI Z-score was significantly reduced in the AVG group and the majority of included studies reported significant results in at least one weight outcome, suggesting AVG can be used to reduce weight or improve body composition in overweight youths. Further studies investigating the long-term sustainability of this change in body composition are needed.

Epidemiology of COVID-19 in Northern Ireland, 26 February 2020-26 April 2020.

This paper describes the epidemiology of coronavirus disease 2019 (COVID-19) in Northern Ireland (NI) between 26 February 2020 and 26 April 2020, and analyses enhanced surveillance and contact tracing data collected between 26 February 2020 and 13 March 2020 to estimate secondary attack rates (SAR) and relative risk of infection among different categories of contacts of individuals with laboratory confirmed severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Our results show that during the study period COVID-19 cumulative incidence and mortality was lower in NI than the rest of the UK. Incidence and mortality were also lower than in the Republic of Ireland (ROI), although these observed differences are difficult to interpret given considerable differences in testing and surveillance between the two nations. SAR among household contacts was 15.9% (95% CI 6.6%-30.1%), over 6 times higher than the SAR among 'high-risk' contacts at 2.5% (95% CI 0.9%-5.4%). The results from logistic regression analysis of testing data on contacts of laboratory-confirmed cases show that household contacts had 11.0 times higher odds (aOR: 11.0, 95% CI 1.7-70.03, P-value: 0.011) of testing positive for SARS-CoV-2 compared to other categories of contacts. These results demonstrate the importance of the household as a locus of SARS-CoV-2 transmission, and the urgency of identifying effective interventions to reduce household transmission.

The epidemiology and management of candidemia in Northern Ireland during 2002-2011, including a 12-month enhanced case review.

In Northern Ireland there are concerns about candidaemia, with rates higher than those reported in England and Wales. Our aim was to explore the epidemiology of candidaemia during a 10 year period and the clinical management upon suspicion of cases during a one year enhanced investigation in Northern Ireland.Candidaemia reports to the Public Health Agency were validated during 2002-2011 and used to examine incidence and antifungal sensitivity trends (during 2007-2011). A clinical proforma was used to collate information for all patients with candidaemia in 2011.The majority (96%) of isolates were captured through voluntary laboratory reporting. There was a year-on-year increase in candidaemia from 2002-2011, from 80 to 131 episodes (incidence rate ratio 1.09 95% CI 1.05-1.13). Rates were highest in males under 1 year and over 75 years. 83/98 (85%) of case notes were available from candidaemia patients during 2011. The most prevalent risk factors were patients on total parenteral nutrition (26 people, 31.3%), surgery in the two months prior to the candidaemia (25 people, 30.1%), significant steroid use in the previous 3 months (24 people, 28.9%) and active neoplastic disease (23 people, 27.7%),This study confirmed an increase in candidaemia rates over time, with the observed incidence in 2011 higher than England and Wales. We identified areas for improvement around the clinical management of candidaemia. We recommend raising the awareness of guidelines for fundoscopy, echocardiography and central venous catheter removal.

Comparing the epidemiology of community- and hospital-associated Clostridium difficile infections in Northern Ireland, 2012-2016: a population data linkage and case-case study.

The burden of community-associated Clostridium difficile infection (CA-CDI) has increased. We aimed to describe the epidemiology of CA-CDI to inform future interventions. We used population-based linked surveillance data from 2012 to 2016 to describe socio-demographic factors, ribotype and mortality for all CA (n = 1303) and hospital-associated (HA, n = 1356) CDI. For 483 community-onset (CO) CA-CDI and 287 COHA-CDI cases, a questionnaire on risk factors was completed and we conducted a case-case study using logistic regression models for univariate and multivariable analysis. CA-CDI cases had lower odds of being male (adjusted odds ratio (AOR) 0.71, 95% confidence interval (CI) 0.58-0.87; P < 0.001), and higher odds of living in rural rather than urban settlement (AOR 1.5, 95% CI 1.1-2.1; P = 0.05) compared with HA-CDI cases. The distribution of ribotypes was similar in both groups with RT078 being most prevalent. CDI-specific death was lower in CA-CDI than HA-CDI (7% vs. 11%, P < 0.001). COCA-CDI had lower odds of having had an outpatient appointment in the previous 4 weeks compared with COHA-CDI (AOR 0.61; 95% CI 0.41-0.9, P = 0.01) and lower odds of being in a care home or hospice when compared with their own home, than COHA-CDI (AOR 0.66; 95% CI 0.45-0.98 and AOR 0.35; 95% CI 0.13-0.92, P = 0.02). Exposure to gastric acid suppressants (50% in COCA-CDI and 55% in COHA-CDI) and antimicrobial therapy (18% in COCA-CDI and 20% in COHA-CDI) prior to CDI was similar. Our analysis of community-onset cases suggests that other risk factors for COHA-CDI may be equally important for COCA-CDI. Opportunities to safely reduce antibiotic and gastric acid suppressants use should be investigated in all healthcare settings.

Prevalence and risk factors associated with Campylobacter spp. and Salmonella enterica in livestock raised on diversified small-scale farms in California.

Diversified farms are operations that raise a variety of crops and/or multiple species of livestock, with the goal of utilising the products of one for the growth of the other, thus fostering a sustainable cycle. This type of farming reflects consumers' increasing demand for sustainably produced, naturally raised or pasture-raised animal products that are commonly produced on diversified farms. The specific objectives of this study were to characterise diversified small-scale farms (DSSF) in California, estimate the prevalence of Salmonella enterica and Campylobacter spp. in livestock and poultry, and evaluate the association between farm- and sample-level risk factors and the prevalence of Campylobacter spp. on DSSF in California using a multilevel logistic model. Most participating farms were organic and raised more than one animal species. Overall Salmonella prevalence was 1.19% (95% confidence interval (CI95) 0.6-2), and overall Campylobacter spp. prevalence was 10.8% (CI95 = 9-12.9). Significant risk factors associated with Campylobacter spp. were farm size (odds ratio (OR)10-50 acres: less than 10 acres = 6, CI95 = 2.11-29.8), ownership of swine (OR = 9.3, CI95 = 3.4-38.8) and season (ORSpring: Coastal summer = 3.5, CI95 = 1.1-10.9; ORWinter: Coastal summer = 3.23, CI95 = 1.4-7.4). As the number of DSSF continues to grow, evaluating risk factors and management practices that are unique to these operations will help identify risk mitigation strategies and develop outreach materials to improve the food safety of animal and vegetable products produced on DSSF.

Health status in Europe: comparison of 24 urban areas to the corresponding 10 countries (EURO-URHIS 2).

Background: : In Europe, over 70% of the population live in urban areas (UAs). Most international comparative health research is done using national level data, as reliable and comparable urban data are often unavailable or difficult to access. This study aims to investigate whether population health is different in UAs compared with their corresponding countries. : Routinely available health-related data were collected by the EURO-URHIS 2 project, for 10 European countries and for 24 UAs within those countries. National and UA level data for 11 health indicators were compared through the calculation of relative difference, and geographical patterns within Europe were investigated using the Mann Whitney U test. Linear regression modelling was used to adjust for population density, gross domestic product and urbanicity. : In general, the urban population in Eastern Europe is less healthy than the Western European urban population. However, people in Eastern Europe have significantly better broad health outcomes in UAs as compared with the corresponding country as a whole, whereas people in Western Europe have generally worse broader health outcomes in UAs. : For most European countries and UAs that were investigated, the national level health status data does not correspond with the health status at UA level. In order to identify health problems in UAs and to provide information for local health policy, health monitoring and international benchmarking should also be conducted at the local level.

Support for the thermal coadaptation hypothesis from the growth rates of Sceloporus jarrovii lizards.

The thermal coadaptation hypothesis posits that ectotherms thermoregulate behaviorally to maintain body temperatures (Tb) that maximize performance, such as net energy gain. Huey's (1982) energetics model describes how food availability and Tb interact to affect net energy gain. We tested the thermal coadaptation hypothesis and Huey's energetics model with growth rates of juvenile Yarrow's spiny lizards (Sceloporus jarrovii). We compared the preferred (selected) Tb range (Tsel) of lizards in high and low energy states to their optimal temperature (To) for growth over nine weeks, and determined whether the To for growth depended on food availability. We also measured the same lizards' resting metabolic rate at five Tbs to test the energetics model assumptions that metabolic cost increases exponentially with Tb and does not differ between energy states. The Tsel of lizards on both diets overlapped with the To for growth. The assumptions of the energetics model were verified, but the To for net energy gain did not depend on food availability. Therefore, we found support for the thermal coadaptation hypothesis. We did not find support for the energetics model, but this may have been due to low statistical power.

Eating in mice with gastric bypass surgery causes exaggerated activation of brainstem anorexia circuit.

BACKGROUND/OBJECTIVE: Obesity and metabolic diseases are at an alarming level globally and increasingly affect children and adolescents. Gastric bypass and other bariatric surgeries have proven remarkably successful and are increasingly performed worldwide. Reduced desire to eat and changes in eating behavior and food choice account for most of the initial weight loss and diabetes remission after surgery, but the underlying mechanisms of altered gut-brain communication are unknown. SUBJECTS/METHODS: To explore the potential involvement of a powerful brainstem anorexia pathway centered around the lateral parabrachial nucleus (lPBN), we measured meal-induced neuronal activation by means of c-Fos immunohistochemistry in a new high-fat diet-induced obese mouse model of Roux-en-Y gastric bypass (RYGB) at 10 and 40 days after RYGB or sham surgery. RESULTS: Voluntary ingestion of a meal 10 days after RYGB, but not after sham surgery, strongly and selectively activates calcitonin gene-related peptide neurons in the external lPBN as well as neurons in the nucleus tractus solitarius, area postrema and medial amygdala. At 40 days after surgery, meal-induced activation in all these areas was greatly diminished and did not reach statistical significance. CONCLUSIONS: The neural activation pattern and dynamics suggest a role of the brainstem anorexia pathway in the early effects of RYGB on meal size and food intake that may lead to adaptive neural and behavioral changes involved in the control of food intake and body weight at a lower level. However, selective inhibition of this pathway will be required for a more causal implication.

Chemistry of free radicals produced by oxidation of endogenous α-aminoketones. A study of 5-aminolevulinic acid and α-aminoacetone by fast kinetics spectroscopy.

BACKGROUND: Excess 5-aminolevulinic acid (ALA) and α-aminoacetone (AA) are implicated in ketosis, porphyrinpathies and diabetes. Pathologic manifestations involve O2⁻, H2O2, OH, enoyl radicals (ALA and AA) and their oxidation end products. METHODS: To characterize enoyl radicals resulting from reaction of OH radicals with ALA and AA, micromolar OH concentrations were produced by pulse radiolysis of ALA and AA in aqueous solutions. RESULTS: ALA and AA react with OH at k=1.5 × 109 M⁻¹s⁻¹. At pH7.4, the ALA absorbance spectrum has a maximum at 330 nm (ε=750 M⁻¹cm⁻¹). This band appears as a shoulder at pH8.3 where two ALA species are present: (NH3)⁺-CH2-CO-CH2-CH2-COO⁻ and NH2-CH2-CO-CH2-CH2-COO⁻ (pKa=8.3). At pH8.3, ALA reacts with oxygen (k=1.4 × 108 M⁻¹s⁻¹) but not with O2⁻. At pH8.3, AA oxidation produces two AA species characterized by an absorbance spectrum with maxima at 330 and 450 nm. ALA and AA are repaired by antioxidants (quercetin (QH), catechin, trolox, ascorbate) which are semi-oxidized (k>10(8)M⁻¹s⁻¹). QH bound to HSA or to apoferritin and ferritin repairs ALA and AA. In O2-saturated apoferritin solutions, Q, O2⁻, AA and reaction product(s) react with QH. CONCLUSIONS: The optical absorption properties and the time evolution of ALA and AA were established for the first time. These radicals and their reaction products may be neutralized by antioxidants free in solution or bound to proteins. GENERAL SIGNIFICANCE: Adjuvant antioxidant administration may be of interest in pathologies related to excess ALA or AA production.

DMRT3 is associated with gait type in Mangalarga Marchador horses, but does not control gait ability.

The Mangalarga Marchador (MM) is a Brazilian horse breed known for a uniquely smooth gait. A recent publication described a mutation in the DMRT3 gene that the authors claim controls the ability to perform lateral patterned gaits (Andersson et al. 2012). We tested 81 MM samples for the DMRT3 mutation using extracted DNA from hair bulbs using a novel RFLP. Horses were phenotypically categorized by their gait type (batida or picada), as recorded by the Brazilian Mangalarga Marchador Breeders Association (ABCCMM). Statistical analysis using the plink toolset (Purcell, 2007) revealed significant association between gait type and the DMRT3 mutation (P = 2.3e-22). Deviation from Hardy-Weinberg equilibrium suggests that selective pressure for gait type is altering allele frequencies in this breed (P = 1.00e-5). These results indicate that this polymorphism may be useful for genotype-assisted selection for gait type within this breed. As both batida and picada MM horses can perform lateral gaits, the DMRT3 mutation is not the only locus responsible for the lateral gait pattern.

Outbreak of invasive pneumococcal disease at a Belfast shipyard in men exposed to welding fumes, Northern Ireland, April-May 2015: preliminary report.

We report an outbreak of four confirmed cases of invasive pneumococcal disease (IPD) in individuals occupationally exposed to welding fumes, at a Belfast shipyard (Northern Ireland). All cases were hospitalised. A high-risk sub-group of 679 workers has been targeted for antibiotic prophylaxis and pneumococcal vaccination. Physicians and public health institutions outside Northern Ireland should be alert to individuals presenting with pneumonia or IPD and recent links to the shipyard, to facilitate early assessment and treatment.

Comparative analysis of SIV-specific cellular immune responses induced by different vaccine platforms in rhesus macaques.

To identify the most promising vaccine candidates for combinatorial strategies, we compared five SIV vaccine platforms including recombinant canary pox virus ALVAC, replication-competent adenovirus type 5 host range mutant RepAd, DNA, modified vaccinia Ankara (MVA), peptides and protein in distinct combinations. Three regimens used viral vectors (prime or boost) and two regimens used plasmid DNA. Analysis at necropsy showed that the DNA-based vaccine regimens elicited significantly higher cellular responses against Gag and Env than any of the other vaccine platforms. The T cell responses induced by most vaccine regimens disseminated systemically into secondary lymphoid tissues (lymph nodes, spleen) and effector anatomical sites (including liver, vaginal tissue), indicative of their role in viral containment at the portal of entry. The cellular and reported humoral immune response data suggest that combination of DNA and viral vectors elicits a balanced immunity with strong and durable responses able to disseminate into relevant mucosal sites.

Humoral immunity induced by mucosal and/or systemic SIV-specific vaccine platforms suggests novel combinatorial approaches for enhancing responses.

Combinatorial HIV/SIV vaccine approaches targeting multiple arms of the immune system might improve protective efficacy. We compared SIV-specific humoral immunity induced in rhesus macaques by five vaccine regimens. Systemic regimens included ALVAC-SIVenv priming and Env boosting (ALVAC/Env); DNA immunization; and DNA plus Env co-immunization (DNA&Env). RepAd/Env combined mucosal replication-competent Ad-env priming with systemic Env boosting. A Peptide/Env regimen, given solely intrarectally, included HIV/SIV peptides followed by MVA-env and Env boosts. Serum antibodies mediating neutralizing, phagocytic and ADCC activities were induced by ALVAC/Env, RepAd/Env and DNA&Env vaccines. Memory B cells and plasma cells were maintained in the bone marrow. RepAd/Env vaccination induced early SIV-specific IgA in rectal secretions before Env boosting, although mucosal IgA and IgG responses were readily detected at necropsy in ALVAC/Env, RepAd/Env, DNA&Env and DNA vaccinated animals. Our results suggest that combined RepAd priming with ALVAC/Env or DNA&Env regimen boosting might induce potent, functional, long-lasting systemic and mucosal SIV-specific antibodies.

Antibodies to gp120 and PD-1 expression on virus-specific CD8+ T cells in protection from simian AIDS.

We compared the relative efficacies against simian immunodeficiency virus (SIV) challenge of three vaccine regimens that elicited similar frequencies of SIV-specific CD4(+) and CD8(+) T-cell responses but differed in the level of antibody responses to the gp120 envelope protein. All macaques were primed with DNA plasmids expressing SIV gag, pol, env, and Retanef genes and were boosted with recombinant modified vaccinia Ankara virus (MVA) expressing the same genes, either once (1 × MVA) or twice (2 × MVA), or were boosted once with MVA followed by a single boost with replication-competent adenovirus (Ad) type 5 host range mutant (Ad5 h) expressing SIV gag and nef genes but not Retanef or env (1 × MVA/Ad5). While two of the vaccine regimens (1 × MVA and 1 × MVA/Ad5) protected from high levels of SIV replication only during the acute phase of infection, the 2 × MVA regimen, with the highest anti-SIV gp120 titers, protected during the acute phase and transiently during the chronic phase of infection. Mamu-A*01 macaques of this third group exhibited persistent Gag CD8(+)CM9(+) effector memory T cells with low expression of surface Programmed death-1 (PD-1) receptor and high levels of expression of genes associated with major histocompatibility complex class I (MHC-I) and MHC-II antigen. The fact that control of SIV replication was associated with both high titers of antibodies to the SIV envelope protein and durable effector SIV-specific CD8(+) T cells suggests the hypothesis that the presence of antibodies at the time of challenge may increase innate immune recruiting activity by enhancing antigen uptake and may result in improvement of the quality and potency of secondary SIV-specific CD8(+) T-cell responses.

NK and CD4+ T cell cooperative immune responses correlate with control of disease in a macaque simian immunodeficiency virus infection model.

Control of infectious disease may be accomplished by successful vaccination or by complex immunologic and genetic factors favoring Ag-specific multicellular immune responses. Using a rhesus macaque model, we evaluated Ag-specific T cell-dependent NK cell immune responses in SIV-infected macaques, designated "controlling" or "noncontrolling" based on long-term chronic viremia levels, to determine whether NK cell effector functions contribute to control of SIV infection. We observed that Gag stimulation of macaque PBMCs induced subset-specific NK cell responses in SIV-controlling but not SIV-noncontrolling animals, as well as that circulatory NK cell responses were dependent on Ag-specific IL-2 production by CD4(+) central memory T cells. NK cell activation was blocked by anti-IL-2-neutralizing Ab and by CD4(+) T cell depletion, which abrogated the Gag-specific responses. Among tissue-resident cells, splenic and circulatory NK cells displayed similar activation profiles, whereas liver and mucosal NK cells displayed a decreased activation profile, similar in SIV-controlling and -noncontrolling macaques. Lack of T cell-dependent NK cell function was rescued in SIV-noncontrolling macaques through drug-mediated control of viremia. Our results indicate that control of disease progression in SIV-controlling macaques is associated with cooperation between Ag-specific CD4(+) T cells and NK cell effector function, which highlight the importance of such cell-to-cell cooperativity in adaptive immunity and suggest that this interaction should be further investigated in HIV vaccine development and other prophylactic vaccine approaches.

Surgical sensation during caesarean section: a qualitative analysis.

BACKGROUND: Caesarean section (CS) is a major abdominal surgery performed usually on a young and healthy population under neuraxial anesthesia with little to no sedation. This creates a distinct surgical experience whereby patients are aware of the surgical process, physical sensations, and their environment. This study aimed to provide an in-depth descriptive assessment of subjective surgical experience during CS under regional anaesthesia. We expected the information gained would enhance our current understanding and better alleviate patient anxiety through informed counselling. METHODS: This qualitative descriptive study was conducted at a Canadian academic centre. Twenty patients participated in semi-structured interviews within a week of CS, using an interview guide developed for this study. Patient medical records were reviewed to collect demographic and surgical information. Thematic analysis was conducted using an inductive approach to determine common themes. RESULTS: Nine themes were identified. Five themes were identified in the category of surgical sensation and four themes were identified in the category of peri-operative education. CONCLUSIONS: Patients commonly experienced pressure and movement sensations at varying intensity, and most did not experience pain. Environmental factors, including sounds and distraction by the newborn, affected perception of surgical sensation. Patients wish to receive pre-operative counselling regarding potential surgical sensations, as well as ongoing communication from their anaesthesiologist. These results can be used to guide informed discussions with patients and direct further investigation in this area.

Replicating adenovirus-simian immunodeficiency virus (SIV) recombinant priming and envelope protein boosting elicits localized, mucosal IgA immunity in rhesus macaques correlated with delayed acquisition following a repeated low-dose rectal SIV(mac251) challenge.

We have shown that sequential replicating adenovirus type 5 host range mutant human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) recombinant priming delivered first intranasally (i.n.) plus orally and then intratracheally (i.t.), followed by envelope protein boosting, elicits broad cellular immunity and functional, envelope-specific serum and mucosal antibodies that correlate with protection from high-dose SIV and simian/human immunodeficiency virus (SHIV) challenges in rhesus macaques. Here we extended these studies to compare the standard i.n./i.t. regimen with additional mucosal administration routes, including sublingual, rectal, and vaginal routes. Similar systemic cellular and humoral immunity was elicited by all immunization routes. Central and effector memory T cell responses were also elicited by the four immunization routes in bronchoalveolar lavage fluid and jejunal, rectal, and vaginal tissue samples. Cellular responses in vaginal tissue were more compartmentalized, being induced primarily by intravaginal administration. In contrast, all immunization routes elicited secretory IgA (sIgA) responses at multiple mucosal sites. Following a repeated low-dose intrarectal (i.r.) challenge with SIV(mac251) at a dose transmitting one or two variants, protection against acquisition was not achieved except in one macaque in the i.r. immunized group. All immunized macaques exhibited reduced peak viremia compared to that of controls, correlated inversely with prechallenge serum antienvelope avidity, antibody-dependent cellular cytotoxicity (ADCC) titers, and percent antibody-dependent cell-mediated viral inhibition. Both antibody avidity and ADCC titers were correlated with the number of exposures required for infection. Notably, we show for the first time a significant correlation of vaccine-induced sIgA titers in rectal secretions with delayed acquisition. Further investigation of the characteristics and properties of the sIgA should elucidate the mechanism leading to this protective effect.