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Sierra Leone is highly endemic for hepatitis B virus (HBV) infection and thus recommends three doses of hepatitis B vaccine (HepB3) from 6 weeks of age but does not recommend a birth dose (HepB-BD) to prevent mother-to-child transmission (MTCT). We evaluated impact of the existing HepB3 schedule and risk for MTCT of HBV. We conducted a community-based serosurvey among 4-30-month-olds, their mothers, and 5-9-year-olds in three districts in Sierra Leone. Participants had an HBV surface antigen (HBsAg) rapid test; all HBsAg-positive and one HBsAg-negative mother per cluster were tested for HBV markers. We collected children's HepB3 vaccination history. Among 1889 children aged 4-30 months, HepB3 coverage was 85% and 20 (1·3% [95% CI 0·8-2·0]) were HBsAg-positive, of whom 70% had received HepB3. Among 2025 children aged 5-9 years, HepB3 coverage was 77% and 32 (1·6% [1·1-2·3]) were HBsAg-positive, of whom 56% had received HepB3. Of 1776 mothers, 169 (9·8% [8·1-11·7]) were HBsAg-positive. HBsAg prevalence was 5·9% among children of HBsAg-positive mothers compared to 0·7% among children of HBsAg-negative mothers (adjusted OR = 10·6 [2·8-40·8]). HBsAg positivity in children was associated with maternal HBsAg (p = 0·026), HBV e antigen (p 0·001), and HBV DNA levels ≥ 200 000 IU/mL (p 0·001). HBsAg prevalence was lower among children than mothers, for whom HepB was not available, suggesting routine infant HepB vaccination has lowered HBV burden. Since HBsAg positivity in children was strongly associated with maternal HBV infection and most of the HBsAg-positive children in the survey received HepB3, HepB-BD may prevent MTCT and chronic HBV infection.

The Western Pacific Region (WPR) established a goal to decrease chronic hepatitis B virus (HBV) infection among children to 1% and to achieve ≥95% hepatitis B vaccine birth dose (HepB-BD) and ≥95% three-dose (HepB3) coverage by 2017. In 2016, we conducted a national serosurvey in the Solomon Islands among 6-7-year-old school children to assess progress towards the control goal and immunity to measles, rubella, tetanus and diphtheria. Eighty schools were selected systematically proportional to their 6-7-year-old population; all 6-7-year-olds were enrolled. We collected basic demographic information and vaccination history. Children were tested for HBV surface antigen (HBsAg) using a rapid test, and for immunity to measles, rubella, tetanus, and diphtheria using a multiplex bead assay. In total, 1,249 out of 1,492 children (84%) were enrolled, among whom 1,169 (94%) underwent HBsAg testing and 1,156 (93%) provided dried blood spots. Almost 80% (n = 982) of enrolled children had vaccination cards, among whom 59% (n = 584) received a timely HepB-BD (within 24 hours of birth), 95% (n = 932) received HepB3, and 90% received vaccines for diphtheria, tetanus, and measles (rubella vaccine was not available at the time). HBsAg prevalence was 3.1% (95% confidence interval (CI): 2.0%-4.9%), with 55% of identified cases from one province. Among 982 children with vaccination cards, HBsAg prevalence was higher among children who had not received a timely HepB-BD and at least two HepB doses compared to those who had (4% vs. 2%). Of 1,156 tested children, immunoprotection estimates were 99% (95% CI: 98%-99%) for measles, 99% (95% CI: 97%-100%) for rubella, 85% (95% CI: 83%-87%) for tetanus, and 51% (95% CI: 47%-55%) for diphtheria. Improving timely HepB-BD coverage and maintaining high HepB3 coverage could help Solomon Islands reach the regional HBV control goal. Low immunity to tetanus and diphtheria suggests the need to introduce booster doses to ensure long-term protection.

Monovalent Hepatitis B vaccine (HepB) is heat stable, making it suitable for storage outside cold chain (OCC) at 37 °C for 1 month. We conducted an OCC project in the Solomon Islands to determine the feasibility of and barriers to national implementation and to evaluate impact on coverage. Healthcare workers at 13 facilities maintained monovalent HepB birth dose (HepB-BD) OCC for up to 28 days over 7 months. Vaccination data were recorded for children born during the project and those born during 7 months before the project. Timely HepB-BD coverage among facility and home births increased from 30% to 68% and from 4% to 24%, respectively. Temperature excursions above 37 °C were rare, but vaccine wastage was high and shortages common. Storing HepB OCC can increase HepB-BD coverage in countries with insufficient cold chain capacity or numerous home births. High vaccine wastage and unreliable vaccine supply must be addressed for successful implementation.

Background All African countries recommend 3 doses of hepatitis B vaccine (HepB3), most at 6, 10, and 14 weeks of age, but few recommend a HepB birth dose (HepB-BD). To evaluate the role of mother to child transmission (MTCT) of hepatitis B virus (HBV) with the 3 dose HepB schedule, we conducted a serosurvey in Sierra Leone among 4–30 month old children and their mothers, and 5–9 year old children. Methods We conducted a multi-stage cluster survey in 3 districts. Enumeration areas (EA) were selected by probability proportional to size, followed by random selection of eligible households to identify 1901 children per age group. We tested all participants for HBV surface antigen (HBsAg) by rapid test and collected children’s HepB vaccination history. Serum from all HBsAg+ mothers and 1 HBsAg- mother per EA was tested for total antibodies to HBV core antigen (anti-HBc), HBsAg, HBV e antigen (HBeAg), and HBV DNA. We assessed the association of HBsAg prevalence with HepB vaccination and maternal HBV markers. Results Among 1889 children aged 4–30 months, 20 (1.3%; 95% CI:0.8%–2.0%) were HBsAg+; HepB3 coverage was 85%. Among 2025 children aged 5–9 years, 32 (1.6%; 95% CI:1.1%–2.3%) were HBsAg+; HepB3 coverage was 77%. Of HBsAg+ children, 70% (14/20) of younger and 56% (18/32) of older children received HepB3. Among 1776 mothers of younger children, 169 (9.8%; 95% CI:8.1%–11.7%) were HBsAg+. HBsAg prevalence for children with HBsAg+ mothers was 5.9% (10/169) and 0.7% (6/1605) for those with HBsAg- mothers (adjusted OR=10.6 [95% CI:2.8–40.8]). Of 139 HBsAg+ mothers, 13 (9%) were HBeAg+ and 126 (91%) had detectable HBV DNA. Maternal HBsAg (p=0.026), HBeAg (p< 0.001), and HBV DNA levels ≥ 200,000 IU/mL (p< 0.001) were associated with HBsAg positivity in younger children (Table 1). Table 1: Association of maternal HBV serological and molecular markers with HBsAg positivity in 4–30-month old children — Sierra Leone hepatitis B serosurvey, 2018 Conclusion HBsAg prevalence was much lower among children than among mothers, for whom HepB would not have been available, indicating that routine infant HepB vaccination has substantially lowered HBV burden. Increasing HepB3 coverage could further reduce HBsAg prevalence among children. As HBsAg positivity in young children was strongly associated with having a mother with active HBV infection and > 50% of HBsAg+ children received HepB3, HepB-BD is needed to prevent MTCT of HBV and chronic HBV infections in children. Disclosures All Authors: No reported disclosures

Member States in the Western Pacific Region (WPR) of the World Health Organization (WHO), are highly vulnerable to emerging influenza viruses that have the potential to cause global pandemics. A well-coordinated strategy for preparedness is required at national and international levels for a robust response and to mitigate the potentially dire consequences of the next influenza pandemic. Of 37 countries and areas in the region, 23 have publically available national pandemic influenza preparedness and response plans; of these, only 17% have been updated in the last five years. However, many plans are pending update and may benefit from integrating some components of the 2017 WHO pandemic influenza risk management guide. Additionally, many plans need to be operationalized to test their functionality. Since 2007, WPRO has conducted annual PanStop exercises to test pandemic containment plans and RC mechanisms in a simulated environment that imitates pandemic events as they unfold. PanStop exercises provide an opportunity for countries to validate policies, protocols and procedures involved in implementing rapid containment (RC) operations, and to identify strengths and opportunities for improvement in planning activities for pandemic influenza. By participating in exercises such as PanStop and the annual regional International Health Regulation (IHR) Crystal Exercise, and subsequently adapting national preparedness plans based on exercise outcomes, WPR continues to improve readiness for the next influenza pandemic.

On May 15, 2014, CDC was notified of two laboratory-confirmed measles cases in the Federated States of Micronesia (FSM), after 20 years with no reported measles. FSM was assisted by the World Health Organization (WHO), the United Nations Children’s Fund (UNICEF), and CDC in investigating suspected cases, identify contacts, conduct analyses to guide outbreak vaccination response, and review vaccine cold chain practices. During February–August, three of FSM’s four states reported measles cases: Kosrae (139 cases), Pohnpei (251), and Chuuk (3). Two thirds of cases occurred among adults aged ≥20 years; of these, 49% had received ≥2 doses of measles-containing vaccine (MCV). Apart from infants aged

Despite 61 contacts with unprotected exposure, no secondary cases occurred., In May 2014, a traveler from the Kingdom of Saudi Arabia was the first person identified with Middle East respiratory syndrome coronavirus (MERS-CoV) infection in the United States. To evaluate transmission risk, we determined the type, duration, and frequency of patient contact among health care personnel (HCP), household, and community contacts by using standard questionnaires and, for HCP, global positioning system (GPS) tracer tag logs. Respiratory and serum samples from all contacts were tested for MERS-CoV. Of 61 identified contacts, 56 were interviewed. HCP exposures occurred most frequently in the emergency department (69%) and among nurses (47%); some HCP had contact with respiratory secretions. Household and community contacts had brief contact (e.g., hugging). All laboratory test results were negative for MERS-CoV. This contact investigation found no secondary cases, despite case-patient contact by 61 persons, and provides useful information about MERS-CoV transmission risk. Compared with GPS tracer tag recordings, self-reported contact may not be as accurate.

Objectives Several outbreaks of serogroup B meningococcal disease have occurred among university students in recent years. In the setting of high coverage of the quadrivalent meningococcal conjugate vaccine and prior to widespread use of serogroup B meningococcal vaccines among adolescents, we conducted surveys to characterize the prevalence and molecular characteristics of meningococcal carriage among university students. Methods Two cross-sectional oropharyngeal carriage surveys were conducted among undergraduates at a Rhode Island university. Isolates were characterized using slide agglutination, real-time polymerase chain reaction (rt-PCR), and whole genome sequencing. Adjusted prevalence ratios and 95% confidence intervals were calculated using Poisson regression to determine risk factors for carriage. Results A total of 1837 oropharyngeal specimens were obtained from 1478 unique participants. Overall carriage prevalence was 12.7–14.6% during the two survey rounds, with 1.8–2.6% for capsular genotype B, 0.9–1.0% for capsular genotypes C, W, or Y, and 9.9–10.8% for nongroupable strains by rt-PCR. Meningococcal carriage was associated with being male, smoking, party or club attendance, recent antibiotic use (inverse correlation), and recent respiratory infections. Conclusions In this university setting, the majority of meningococcal carriage was due to nongroupable strains, followed by serogroup B. Further evaluation is needed to understand the dynamics of serogroup B carriage and disease among university students.

OBJECTIVE: To assess the safety of meningococcal group B (MenB)-4C vaccine. PARTICIPANTS: Undergraduates, dormitory residents, and persons with high-risk medical conditions received the MenB-4C vaccine two-dose series during mass vaccination clinics from 12/2013 through 11/2014. METHODS: Adverse events (AEs) were identified by 15 minutes of observation postvaccination, spontaneous reports, surveys, and hospital surveillance. Causality was assessed for serious adverse events (SAEs). RESULTS: 16,974 persons received 31,313 MenB-4C doses. The incidence of syncope during the 15-minutes post-dose 1 was 0.88/1000 persons. 2% of participants spontaneously reported an AE (most common were arm pain and fever). 3 SAEs were suspected of being caused by the vaccine, including one case of anaphylaxis. CONCLUSIONS: Most AEs reported were nonserious and consistent with previous clinical trial findings. Measures to prevent injury from syncope and to treat anaphylaxis should be available wherever vaccines are administered. Our safety evaluation supports the use of MenB-4C in response to outbreaks.

Background. The Middle East respiratory syndrome coronavirus (MERS-CoV) was discovered September 2012 in the Kingdom of Saudi Arabia (KSA). The first US case of MERS-CoV was confirmed on 2 May 2014. Methods. We summarize the clinical symptoms and signs, laboratory and radiologic findings, and MERS-CoV–specific tests. Results. The patient is a 65-year-old physician who worked in a hospital in KSA where MERS-CoV patients were treated. His illness onset included malaise, myalgias, and low-grade fever. He flew to the United States on day of illness (DOI) 7. His first respiratory symptom, a dry cough, developed on DOI 10. On DOI 11, he presented to an Indiana hospital as dyspneic, hypoxic, and with a right lower lobe infiltrate on chest radiography. On DOI 12, his serum tested positive by real-time reverse transcription polymerase chain reaction (rRT-PCR) for MERS-CoV and showed high MERS-CoV antibody titers, whereas his nasopharyngeal swab was rRT-PCR negative. Expectorated sputum was rRT-PCR positive the following day, with a high viral load (5.31 × 106 copies/mL). He was treated with antibiotics, intravenous immunoglobulin, and oxygen by nasal cannula. He was discharged on DOI 22. The genome sequence was similar (>99%) to other known MERS-CoV sequences, clustering with those from KSA from June to July 2013. Conclusions. This patient had a prolonged nonspecific prodromal illness before developing respiratory symptoms. Both sera and sputum were rRT-PCR positive when nasopharyngeal specimens were negative. US clinicians must be vigilant for MERS-CoV in patients with febrile and/or respiratory illness with recent travel to the Arabian Peninsula, especially among healthcare workers.

This report highlights the first two cases of MERS coronavirus in the United States. Although these patients were not transplant recipients, it is important for transplant professionals to be aware of this infection and to consider it when evaluating patients with respiratory illnesses and travel to the Arabian peninsula.

The World Health Organization (WHO) African Region has approximately 100 million people with chronic hepatitis B virus (HBV) infection. This review describes the status of hepatitis B control in the Region. We present hepatitis B vaccine (HepB) coverage data and from available data in the published literature, the impact of HepB vaccination on hepatitis B surface antigen (HBsAg) prevalence, a marker of chronic infection, among children, HBsAg prevalence in pregnant women, and risk of perinatal transmission. Lastly, we describe challenges with HepB birth dose (HepB-BD) introduction reported in the Region, and propose strategies to increase coverage. In 2015, regional three dose HepB coverage was 76%, and 16(34%) of 47 countries reported ≥ 90% coverage. Overall, 11 countries introduced HepB-BD; only nine provide universal HepB-BD, and of these, five reported ≥ 80% coverage. From non-nationally representative serosurveys among children, HBsAg prevalence was lower among children born after HepB introduction compared to those born before HepB introduction. However, some studies still found HBsAg prevalence to be above 2%. From limited surveys among pregnant women, the median HBsAg prevalence varied by country, ranging from 1.9% (Madagascar) to 16.1% (Niger); hepatitis B e antigen (HBeAg) prevalence among HBsAg-positive women ranged from 3.3% (Zimbabwe) to 28.5% (Nigeria). Studies in three countries indicated that the risk of perinatal HBV transmission was associated with HBeAg expression or high HBV DNA viral load. Major challenges for timely HepB-BD administration were poor knowledge of or lack of national HepB-BD vaccination guidelines, high prevalence of home births, and unreliable vaccine supply. Overall, substantial progress has been made in the region. However, countries need to improve HepB3 coverage and some countries might need to consider introducing the HepB-BD to help achieve the regional hepatitis B control goal of < 2% HBsAg prevalence among children < 5 years old by 2020. To facilitate HepB-BD introduction and improve timely coverage, strategies are needed to reach both facility-based and home births. Strong political commitment, clear policy recommendations and staff training on HepB-BD administration are also required. Furthermore, high quality nationally representative serosurveys among children are needed to inform decision makers about progress towards the regional control goal.

In the late summer of 2014, it became apparent that improved preparedness was needed for Ebola virus disease (Ebola) in at-risk countries surrounding the three highly affected West African countries (Guinea, Sierra Leone, and Liberia). The World Health Organization (WHO) identified 14 nearby African countries as high priority to receive technical assistance for Ebola preparedness; two additional African countries were identified at high risk for Ebola introduction because of travel and trade connections. To enhance the capacity of these countries to rapidly detect and contain Ebola, CDC established the High-Risk Countries Team (HRCT) to work with ministries of health, CDC country offices, WHO, and other international organizations. From August 2014 until the team was deactivated in May 2015, a total of 128 team members supported 15 countries in Ebola response and preparedness. In four instances during 2014, Ebola was introduced from a heavily affected country to a previously unaffected country, and CDC rapidly deployed personnel to help contain Ebola. The first introduction, in Nigeria, resulted in 20 cases and was contained within three generations of transmission; the second and third introductions, in Senegal and Mali, respectively, resulted in no further transmission; the fourth, also in Mali, resulted in seven cases and was contained within two generations of transmission. Preparedness activities included training, developing guidelines, assessing Ebola preparedness, facilitating Emergency Operations Center establishment in seven countries, and developing a standardized protocol for contact tracing. CDC's Field Epidemiology Training Program Branch also partnered with the HRCT to provide surveillance training to 188 field epidemiologists in Cote d'Ivoire, Guinea-Bissau, Mali, and Senegal to support Ebola preparedness. Imported cases of Ebola were successfully contained, and all 15 priority countries now have a stronger capacity to rapidly detect and contain Ebola.The activities summarized in this report would not have been possible without collaboration with many U.S and international partners (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/partners.html).

Purpose During March–November 2013, five cases of serogroup B meningococcal disease occurred among University A undergraduates. The Centers for Disease Control and Prevention used the unlicensed MenB-4C (Bexsero, Novartis Vaccines), a serogroup B meningococcal vaccine, to control the outbreak. All undergraduates (n = 19,257) were offered two doses; 51% of undergraduates received ≥1 dose of MenB-4C. We conducted a knowledge, attitudes, and practice survey to understand which factors and sources of information impacted their decision on whether or not to receive vaccine. Methods An anonymous online survey was sent to University A undergraduates. The survey was implemented in June 2–30, 2014, and covered demographics, MenB-4C vaccination decision, and sources of information. Descriptive analyses were conducted. Results A total of 1,341 students completed the survey (response rate = 7.0%), of these 873 received ≥1 dose of MenB-4C. Among vaccinated respondents, the predominant reasons for receiving vaccine were knowledge of disease severity, parental recommendation, and believing that vaccination offered the best protection. Among unvaccinated respondents, the predominant reasons for not receiving vaccine were perception of low disease risk and concern over vaccine newness and safety. Respondents' top primary sources of information were e-mails from the university followed by their parents. Conclusions Reasons behind respondents' decision to receive an unlicensed vaccine were similar to those reported for routinely recommended vaccines. Given the challenges around communicating the importance of receiving a vaccine that is not routinely recommended, respondents' primary sources of information, the university and their parents, could be targeted to improve coverage rates.

Background. Vaccination is the best measure to protect the population against a potential influenza H5N1 pandemic, but 2 doses of vaccine are needed to elicit protective immune responses. An immunological marker for H5N1 vaccine effectiveness is needed for early identification of the best vaccine candidate. Methods. We conducted a phase I clinical trial of a virosomal H5N1 vaccine adjuvanted with Matrix M. Sixty adult volunteers were vaccinated intramuscularly with 2 doses of either 30 μg hemagglutinin (HA) alone or with 1.5, 7.5, or 30 μg HA and Matrix M adjuvant (50 μg). The humoral response was measured by the hemagglutination inhibition (HI), microneutralization (MN), and single radial hemolysis (SRH) assays, and the CD4 + T-helper 1 (Th1)–cell response was measured by intracellular staining for the cytokines interleukin 2, interferon γ, and tumor necrosis factor α. Results. The adjuvanted vaccine effectively induced CD4 + Th1-cell responses, and the frequency of influenzaspecific Th1 cells after the first vaccine dose predicted subsequent HI, MN, and SRH seroprotective responses after the second vaccination. Conclusions. These results support early identification of Th1-cell responses as a predictive biomarker for an efficient vaccine response, which could have great implications for early identification of persons with low or no response to vaccine when evaluating future pandemic influenza vaccines. Clinical Trials Registration. NCT00868218.

The double-stranded RNA-activated protein kinase (PKR) is a key regulator of protein translation, interferon (IFN) expression and cell survival. Upon infection of vertebrate cells in continuous culture, the alphavirus Semliki Forest virus (SFV) initiates apoptosis and IFN synthesis. To determine the effect of PKR on SFV infection, we studied the course of infection in wild-type (wt) mice, mice with a genetic deletion of PKR (PKR−/−) and mouse embryo fibroblasts (MEFs) derived from these mice. In MEFs, PKR delayed virus protein synthesis, production of infectious virus and caspase-3-activated cell death and reduced the yield of infectious virus by 90 %. Small interfering RNA suppression of PKR levels in NIH-3T3 cells also reduced virus production and apoptosis. In MEFs, PKR was not required for initiation of IFN-β gene transcription, but contributed strongly to the magnitude of this response. Levels of IFN-β transcripts in PKR−/− MEFs at 8 h were 80 % lower than those in wt MEFs and levels of functional IFN at 24 h were 95 % lower. Following infection of wt and PKR−/− mice, SFV4 and SFV A7(74) were avirulent. PKR increased levels of serum IFN and the rate of clearance of infectious virus from the brain. In summary, in response to SFV, PKR exerts an early antiviral effect that delays virus protein production and release of infectious virus and, whilst PKR is not required for induction of apoptosis or activation of the type I IFN response, it strongly augments the type I IFN response and contributes to clearance of infectious virus from the mouse brain.

BACKGROUND:In the United States, the proportion of Bordetella pertussis isolates lacking pertactin, a component of acellular pertussis vaccines, increased from 14% in 2010 to 85% in 2012. The impact on vaccine effectiveness (VE) is unknown.METHODS:We conducted 2 matched case-control evaluations in Vermont to assess VE of the 5-dose diphtheria, tetanus, and acellular pertussis vaccine (DTaP) series among 4- to 10-year-olds, and tetanus, diphtheria, and acellular pertussis vaccine (Tdap) among 11- to 19-year-olds. Cases reported during 2011 to 2013 were included. Three controls were matched to each case by medical home, and additionally by birth year for the Tdap evaluation. Vaccination history was obtained from medical records and parent interviews. Odds ratios (OR) were calculated by using conditional logistic regression; VE was estimated as (1-OR) × 100%. Pertactin status was determined for cases with available isolates.RESULTS:Overall DTaP VE was 84% (95% confidence interval [CI] 58%–94%). VE within 12 months of dose 5 was 90% (95% CI 71%–97%), declining to 68% (95% CI 10%–88%) by 5–7 years post-vaccination. Overall Tdap VE was 70% (95% CI 54%–81%). Within 12 months of Tdap vaccination, VE was 76% (95% CI 60%–85%), declining to 56% (95% CI 16%–77%) by 2–4 years post-vaccination. Of cases with available isolates, >90% were pertactin-deficient.CONCLUSIONS:Our DTaP and Tdap VE estimates remain similar to those found in other settings, despite high prevalence of pertactin deficiency in Vermont, suggesting these vaccines continue to be protective against reported pertussis disease.

Semliki Forest virus (SFV) infection of the mouse provides a powerful model to study the pathogenesis of virus encephalitis. SFV and other alphavirus-based vector systems are increasingly used in biotechnology and medicine. This study analysed the strong susceptibility of this virus to type I interferon (IFN) responses. Following intraperitoneal infection of adult mice, SFV strain A7(74) was efficiently (100 %) neuroinvasive. In contrast, SFV4 was poorly (21 %) neuroinvasive. Upon entry into the brain, both viruses activated type I IFN responses. As determined by quantitative RT-PCR, activation of the IFN-αgene was proportional to virus RNA load. An intact type I IFN system was required for protection against both strains of SFV. IFN strongly curtailed virus spread in many cell types and in many tissues. In mice with an intact type I IFN system, infected cells were rarely observed and tissue tropism was difficult to determine. In the absence of a functional type I IFN system, the tropism and the potential for rapid and widespread infection of this virus was revealed. Virus infection was readily observed in the myocardium, endocardium, exocrine pancreas, adipose tissue, smooth muscle cells and in the brain in meningeal cells, ependymal cells and oligodendrocytes. In the brains of mice with and without type I IFN responses, virus infection of neurons remained rare and focal, indicating that the previously described restricted replication of SFV A7(74) in neurons is not mediated by type I IFN responses.

The type I interferons (IFNs) are potent mediators of antiviral immunity, and many viruses have developed means to block their expression or their effects. Semliki Forest virus (SFV) infection induces rapid and profound silencing of host cell gene expression, a process believed to be important for the inhibition of the IFN response. In SFV-infected cells, a large proportion of the nonstructural protein nsp2 is found in the nucleus, but a role for this localization has not been described. In this work we demonstrate that a viral mutant, SFV4-RDR, in which the nuclear localization sequence of nsp2 has been rendered inactive, induces a significantly more robust IFN response in infected cells. This mutant virus replicates at a rate similar to that of the parental SFV4 strain and also shuts off host cell gene expression to similar levels, indicating that the general cellular shutoff is not responsible for the inhibition of IFN expression. Further, the rate of virus-induced nuclear translocation of early IFN transcription factors was not found to differ between the wild-type and mutant viruses, indicating that the effect of nsp2 is at a later stage. These results provide novel information about the mode of action of this viral IFN antagonist.

Background Influenza H5N1 virus constitutes a pandemic threat and development of effective H5N1 vaccines is a global priority. Anti-influenza antibodies directed towards the haemagglutinin (HA) define a correlate of protection. Both antibody concentration and avidity may be important for virus neutralization and resolving influenza disease. Methods We conducted a phase I clinical trial of a virosomal H5N1 vaccine adjuvanted with the immunostimulating complex Matrix M™. Sixty adults were intramuscularly immunized with two vaccine doses (21 days apart) of 30 μg HA alone or 1.5, 7.5 or 30 μg HA adjuvanted with Matrix M™. Serum H5 HA1-specific antibodies and virus neutralization were determined at days 0, 21, 42, 180 and 360 and long-term memory B cells at day 360 post-vaccination. The binding of the HA specific antibodies was measured by avidity NaSCN-elution ELISA and surface plasmon resonance (SPR). Results The H5 HA1-specific IgG response peaked after the second dose (day 42), was dominated by IgG1 and IgG3 and was highest in the adjuvanted vaccine groups. IgG titres correlated significantly with virus neutralization at all time points (Spearman r ≥ 0.66, p

The avian influenza H5 virus epizootic continues to cause zoonosis with human fatalities, highlighting the continued need for pandemic preparedness against this subtype. This study evaluated the tolerability and immunogenicity of a Matrix M™ adjuvanted virosomal H5N1 vaccine in a phase I clinical trial. Sixty healthy adults were vaccinated intramuscularly with two doses of influenza H5N1 (NIBRG-14) virosomal vaccine alone (30 μg haemagglutinin (HA)) or 1.5, 7.5 or 30 μg HA formulated with 50 μg Matrix M™ adjuvant. The antibody response was analysed by haemagglutination inhibition (HI), microneutralisation (MN) and single radial haemolysis (SRH) assays. The vaccine was well tolerated in all groups but injection site pain was more frequently observed in the Matrix M™ adjuvanted groups. The vaccine elicited homologous and heterologous H5N1-specific antibody responses and the Matrix M™ adjuvanted formulations met all the EU regulatory criteria. In conclusion, Matrix M™ adjuvant was well tolerated and augmented the antibody response allowing considerable dose sparing down to 1.5 μg HA.