Preventing Hepatitis B Virus Infection Among U.S. Military Personnel: Potential Impact of a 2-Dose Versus 3-Dose Vaccine on Medical Readiness.

INTRODUCTION: Hepatitis B, a major public health issue worldwide, has been associated with serious clinical outcomes. Military personnel are at particular risk for hepatitis B, such that hepatitis B vaccination is part of the accession process for new recruits. Although lost time costs and medical cost avoidance have been used by the U.S. Military to guide their decision-making protocols, this has not been applied to hepatitis B vaccination costs. Herein, a decision-analytic model is used to compare the effective vaccine protection rates and vaccine and operational costs of 2-dose versus 3-dose hepatitis B vaccine regimens in a population of recruits from the U.S. Marine Corps Recruit Depot, Parris Island. METHODS: A decision-analytic model was developed to assess the expected levels of adherence, seroprotection, and vaccination and operational costs of a cohort of recruits vaccinated with either a 2-dose (HepB-CpG) vaccine for those eligible (scenario 1) or a 3-dose (HepB-Alum) vaccine (scenario 2). De-identified data from 23,004 recruits at the Marine Corps Recruit Depot, Parris Island, in 2018 and 2019 were used to provide real-world data on age distribution and vaccination status. Other inputs included published data on adherence for hepatitis B vaccines and seroprotection rates for HepB-CpG and HepB-Alum in relation to the number of doses received. Costs included direct medical costs of the hepatitis B vaccination and operational costs such as missed training time. RESULTS: After receipt of two vaccine doses, 92% of recruits in scenario 1 (HepB-CpG group) were expected to be protected against hepatitis B within 1 month of receiving the second dose, compared with 24% of recruits in scenario 2 (HepB-Alum group), leaving 76% of Marine recruits unprotected if using HepB-Alum during the intervening 5-month period between doses 2 and 3. Over the study period, HepB-CpG was estimated to provide cost savings of $744,509 (17.3% cost reduction) compared with HepB-Alum, with the cost of missed training time being the most influential driver of the cost difference between the two vaccination schedules. CONCLUSIONS: Findings from this model suggest that vaccination with the 2-dose HepB-CpG vaccine may provide earlier and higher protection against hepatitis B compared with the 3-dose vaccine (HepB-Alum). A 2-dose vaccination strategy incorporated as part of individual medical readiness has the potential to not only increase protection but also confer economic savings among military recruits at risk for hepatitis B infection.

Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection.

Male sex is a major risk factor for SARS-CoV-2 infection severity. To understand the basis for this sex difference, we studied SARS-CoV-2 infection in a young adult cohort of United States Marine recruits. Among 2,641 male and 244 female unvaccinated and seronegative recruits studied longitudinally, SARS-CoV-2 infections occurred in 1,033 males and 137 females. We identified sex differences in symptoms, viral load, blood transcriptome, RNA splicing, and proteomic signatures. Females had higher pre-infection expression of antiviral interferon-stimulated gene (ISG) programs. Causal mediation analysis implicated ISG differences in number of symptoms, levels of ISGs, and differential splicing of CD45 lymphocyte phosphatase during infection. Our results indicate that the antiviral innate immunity set point causally contributes to sex differences in response to SARS-CoV-2 infection. A record of this paper's transparent peer review process is included in the supplemental information.

SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures.

BACKGROUND: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. METHODS: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. RESULTS: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. CONCLUSIONS: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.

Lessons Learned From a Prospective Observational Study of U.S. Marine Recruits During a Supervised Quarantine, Spring‒Fall 2020.

Introduction: Quarantining is commonly used to mitigate the spread of SARS-CoV-2. However, questions remain regarding what specific interventions are most effective. Methods: After a 2-week home quarantine, U.S. Marine Corps recruits underwent a supervised 2-week quarantine at a hotel from August 11 to September 21, 2020. All recruits were assessed for symptoms through oral questioning and had their temperatures checked daily. Study participants answered a written clinical questionnaire and were tested for SARS-CoV-2 by polymerase chain reaction shortly after arrival in quarantine and on Days 7 and 14. The results were compared with those of a previously reported Marine-supervised quarantine at a college campus from May until July 2020 utilizing the same study, laboratory, and statistical procedures. Results: A total of 1,401 of 1,514 eligible recruits (92.5%) enrolled in the study, 93.1% of whom were male. At the time of enrollment, 12 of 1,401 (0.9%) participants were polymerase chain reaction positive for SARS-CoV-2, 9 of 1,376 (0.7%) were positive on Day 7, and 1 of 1,358 (0.1%) was positive on Day 14. Only 12 of 22 (54.5%) participants endorsed any symptoms on a study questionnaire, and none of the participants had an elevated temperature or endorsed symptoms during daily screening for SARS-CoV-2. Participation rate (92%) was much greater than the approximately 58.8% (1,848 of 3,143) rate observed in the previous Marine-supervised college campus quarantine, suggesting the changing attitudes of recruits during the pandemic (p<0.001). Approximately 1% of participants were quantitative polymerase chain reaction positive after self-quarantine in both studies. Conclusions: Key findings include the shifting attitudes of young adults during the pandemic, the limitations of self-quarantine, and the ineffectiveness of daily temperature and symptom screening to identify SARS-CoV-2‒positive recruits.

Antibody Responses to SARS-CoV-2 Following an Outbreak Among Marine Recruits With Asymptomatic or Mild Infection.

We investigated serological responses following a SARS-CoV-2 outbreak in spring 2020 on a US Marine recruit training base. 147 participants that were isolated during an outbreak of respiratory illness were enrolled in this study, with visits approximately 6 and 10 weeks post-outbreak (PO). This cohort is comprised of young healthy adults, ages 18-26, with a high rate of asymptomatic infection or mild symptoms, and therefore differs from previously reported longitudinal studies on humoral responses to SARS-CoV-2, which often focus on more diverse age populations and worse clinical presentation. 80.9% (119/147) of the participants presented with circulating IgG antibodies against SARS-CoV-2 spike (S) receptor-binding domain (RBD) at 6 weeks PO, of whom 97.3% (111/114) remained positive, with significantly decreased levels, at 10 weeks PO. Neutralizing activity was detected in all sera from SARS-CoV-2 IgG positive participants tested (n=38) at 6 and 10 weeks PO, without significant loss between time points. IgG and IgA antibodies against SARS-CoV-2 RBD, S1, S2, and the nucleocapsid (N) protein, as well neutralization activity, were generally comparable between those participants that had asymptomatic infection or mild disease. A multiplex assay including S proteins from SARS-CoV-2 and related zoonotic and human endemic betacoronaviruses revealed a positive correlation for polyclonal cross-reactivity to S after SARS-CoV-2 infection. Overall, young adults that experienced asymptomatic or mild SARS-CoV-2 infection developed comparable humoral responses, with no decrease in neutralizing activity at least up to 10 weeks after infection.

SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.

BACKGROUND: Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection. METHODS: This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM). CHARM included predominantly male US Marine recruits, aged 18-20 years, following a 2-week unsupervised quarantine at home. After the home quarantine period, upon arrival at a Marine-supervised 2-week quarantine facility (college campus or hotel), participants were enrolled and were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein ELISA. Participants also completed a questionnaire consisting of demographic information, risk factors, reporting of 14 specific COVID-19-related symptoms or any other unspecified symptom, and brief medical history. SARS-CoV-2 infection was assessed by PCR at weeks 0, 1, and 2 of quarantine and participants completed a follow-up questionnaire, which included questions about the same COVID-19-related symptoms since the last study visit. Participants were excluded at this stage if they had a positive PCR test during quarantine. Participants who had three negative swab PCR results during quarantine and a baseline serum serology test at the beginning of the supervised quarantine that identified them as seronegative or seropositive for SARS-CoV-2 then went on to basic training at Marine Corps Recruit Depot-Parris Island. Three PCR tests were done at weeks 2, 4, and 6 in both seropositive and seronegative groups, along with the follow-up symptom questionnaire and baseline neutralising antibody titres on all subsequently infected seropositive and selected seropositive uninfected participants (prospective study period). FINDINGS: Between May 11, 2020, and Nov 2, 2020, we enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants, 2825 (92%) of whom were men, were then followed up during the prospective study period after quarantine for 6 weeks. Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11-0·28; p<0·001). Among seropositive recruits, infection was more likely with lower baseline full-length spike protein IgG titres than in those with higher baseline full-length spike protein IgG titres (hazard ratio 0·45 [95% CI 0·32-0·65]; p<0·001). Infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants (ORF1ab gene cycle threshold difference 3·95 [95% CI 1·23-6·67]; p=0·004). Among seropositive participants, baseline neutralising titres were detected in 45 (83%) of 54 uninfected and in six (32%) of 19 infected participants during the 6 weeks of observation (ID50 difference p<0·0001). INTERPRETATION: Seropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralisation activity or immunity against subsequent infection. These findings might be relevant for optimisation of mass vaccination strategies. FUNDING: Defense Health Agency and Defense Advanced Research Projects Agency.

SARS-CoV-2 Transmission among Marine Recruits during Quarantine.

BACKGROUND: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults. METHODS: We investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections. RESULTS: A total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon. CONCLUSIONS: Among Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons. (Funded by the Defense Health Agency and others.).

Reshaping US Navy Pacific response in mitigating disaster risk in South Pacific Island nations: adopting community-based disaster cycle management.

The US Department of Defense continues to deploy military assets for disaster relief and humanitarian actions around the world. These missions, carried out through geographically located Combatant Commands, represent an evolving role the US military is taking in health diplomacy, designed to enhance disaster preparedness and response capability. Oceania is a unique case, with most island nations experiencing "acute-on-chronic" environmental stresses defined by acute disaster events on top of the consequences of climate change. In all Pacific Island nation-states and territories, the symptoms of this process are seen in both short- and long-term health concerns and a deteriorating public health infrastructure. These factors tend to build on each other. To date, the US military's response to Oceania primarily has been to provide short-term humanitarian projects as part of Pacific Command humanitarian civic assistance missions, such as the annual Pacific Partnership, without necessarily improving local capacity or leaving behind relevant risk-reduction strategies. This report describes the assessment and implications on public health of large-scale humanitarian missions conducted by the US Navy in Oceania. Future opportunities will require the Department of Defense and its Combatant Commands to show meaningful strategies to implement ongoing, long-term, humanitarian activities that will build sustainable, host nation health system capacity and partnerships. This report recommends a community-centric approach that would better assist island nations in reducing disaster risk throughout the traditional disaster management cycle and defines a potential and crucial role of Department of Defense's assets and resources to be a more meaningful partner in disaster risk reduction and community capacity building.

Physician practice behavior and practice guidelines: using unannounced standardized patients to gather data.

BACKGROUND: Measuring actual practice behaviors of physicians, particularly as they relate to established clinical guidelines, is challenging. Standardized patients provide one method of collecting such data. OBJECTIVE: To demonstrate the use of unannounced standardized patients in gathering data that may address adherence to guidelines in an office setting. DESIGN: Unannounced standardized patients (SPs) simulating an initial type 2 diabetic visit presented to community offices of 32 internists as "real" patients to record physicians' evaluation and management. PARTICIPANTS: Unannounced SPs presented to the office of 32 internists as "real" patients. MEASUREMENTS: Unannounced SPs, simulating type 2 diabetics, completed a standardized assessment sheet, based on ADA guidelines to record physicians' evaluation and management following an initial visit. Patient charts were also reviewed to determine if evaluation adhered to the guidelines. RESULTS: Unannounced SPs recorded 56 visits with 32 community internists; all SPs remained undetected. All physicians asked SPs about medications. At least 50% of physicians asked about home blood sugar monitoring, last eye exam, smoking, edema, and told patients to stop smoking. Less than 50% of physicians asked about parasthesias, performed fundoscopy, examined feet, referred the patient to a diabetic educator or ophthalmologist, or gave patients suggestions regarding glucose monitoring or exercise. HbA1c was ordered in 78%, metabolic profiles in 86%, and urinalysis/microalbumin in 41% of patients. CONCLUSIONS: Unannounced standardized patients can successfully collect important data regarding physician practices in community settings. This method may be helpful in assessing physician adherence to established clinical practice guidelines.

Differential identification of Ascogregarina species (Apicomplexa: Lecudinidae) in Aedes aegypti and Aedes albopictus (Diptera: Culicidae) by polymerase chain reaction.

We report 2 polymerase chain reaction (PCR)-based methods for distinguishing morphologically similar gregarine species based on amplification of variable regions of the internal transcribed spacer region of ribosomal DNA. The gregarines we investigated were Ascogregarina barretti (Vavra), A. culicis (Ross), and A. taiwanensis (Lien and Levine), parasites of the mosquitoes Ochlerotatus triseriatus (Say), Aedes aegypti (Linnaeus), and Ae. albopictus (Skuse), respectively. These 3 important vector mosquitoes often utilize the same container habitats, where larval development and infection by the parasite occurs, leaving ample opportunity for cross-species gregarine infection. Because previous studies have shown that the parasites A. culicis and A. taiwanensis variably affect fitness in both normal and abnormal mosquito hosts, distinguishing parasite infection and species is important. The task is complicated by the fact that these 2 parasite species are virtually identical in morphology, whereas A. barretti is morphologically distinct. Of the 2 PCR-based assays reported here, the first provides a rapid, sensitive, and straight-forward means of general ascogregarine detection based on a single PCR amplification. The second method provides a means of differentiation between A. culicis and A. taiwanensis based on a species-specific PCR assay. Together, these assays allow whole mosquitoes to be tested for the presence of Ascogregarina species as well as identification of both A. culicis and A. taiwanensis singly or in dual infections.