Vaccination of health care workers to protect patients at increased risk for acute respiratory disease.

Health care workers (HCWs) may transmit respiratory infection to patients. We assessed evidence for the effectiveness of vaccinating HCWs to provide indirect protection for patients at risk for severe or complicated disease after acute respiratory infection. We searched electronic health care databases and sources of gray literature by using a predefined strategy. Risk for bias was assessed by using validated tools, and results were synthesized by using a narrative approach. Seventeen of the 12,352 identified citations met the full inclusion criteria, and 3 additional articles were identified from reference or citation tracking. All considered influenza vaccination of HCWs, and most were conducted in long-term residential care settings. Consistency in the direction of effect was observed across several different outcome measures, suggesting a likely protective effect for patients in residential care settings. However, evidence was insufficient for us to confidently extrapolate this to other at-risk patient groups.

Influenza and COVID-19: What does co-existence mean?

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 continues to have a major impact on healthcare and social systems throughout the world. As the clinical and epidemiological features of COVID-19 have many parallels with influenza, it is important to ensure optimal management of both respiratory diseases as we anticipate their continued co-circulation. In particular, there is a need to ensure that effective surveillance and diagnostic capacities are in place to monitor these and other respiratory viruses, as this will underpin decisions on the appropriate clinical management of the respective diseases. As such, we propose a series of key recommendations for stakeholders, public health authorities, primary care physicians and surveillance bodies that will help mitigate the combined risks of concurrent influenza epidemics and the COVID-19 pandemic. We advocate the judicious use of influenza vaccines and antivirals, particularly among groups at high risk of complications, with healthcare workers also considered a priority for vaccination. It is likely that the increased use of emerging technologies such as telemedicine and contact tracing will permanently change our approach to managing infectious disease. The use of these technologies, alongside existing pharmaceutical strategies, will ensure that we achieve a holistic approach to the global public health measures needed to deal with the combined threat of influenza and COVID-19. Ensuring that this approach is optimal will be key as we move from a reactive pandemic response towards preparing for the long-term management of the remarkable clinical burden associated with these respiratory pathogens.

Vaccinating pregnant women against influenza needs to be a priority for all countries: An expert commentary.

BACKGROUND: In 2012, the World Health Organization recommended influenza vaccination for all pregnant women worldwide and the prioritisation of pregnant women in national influenza vaccination programmes. Nevertheless, vaccination rates in pregnant women often remain much lower than national targets. OBJECTIVES: To assess the benefits and risks associated with influenza infection and vaccination during pregnancy, and to consider obstacles that work against influenza vaccine uptake during pregnancy. RESULTS: There is strong evidence that maternal and foetal outcomes can be compromised if women develop influenza infections during pregnancy. Influenza vaccines have been administered to millions of pregnant women and have demonstrated benefits in terms of disease prevention in mothers and their infants. There is a consensus amongst several recommending authorities that influenza vaccines may be safely administered during all stages of pregnancy. Healthcare professionals are recognised as the most important influencers of vaccine uptake, being well placed to recommend vaccination and directly address safety concerns. CONCLUSIONS: Despite data supporting the value of influenza vaccination during pregnancy, vaccine uptake remains low globally. Low uptake appears to be largely due to ineffective communication with pregnant women about the risks and benefits of influenza vaccination. A graphical abstract is available online.

Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia.

BACKGROUND: This study was designed to evaluate the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) against culture-confirmed influenza in children 12 to <36 months of age during 2 consecutive influenza seasons at multiple sites in Asia. METHODS: In year 1, 3174 children 12 to <36 months of age were randomized to receive 2 doses of CAIV-T (n = 1900) or placebo (n = 1274) intranasally > or =28 days apart. In year 2, 2947 subjects were rerandomized to receive 1 dose of CAIV-T or placebo. RESULTS: Mean age at enrollment was 23.5 +/- 7.4 months. In year 1, efficacy of CAIV-T compared with placebo was 72.9% [95% confidence interval (CI): 62.8-80.5%] against antigenically similar influenza subtypes, and 70.1% (95% CI: 60.9-77.3%) against any strain. In year 2, revaccination with CAIV-T demonstrated significant efficacy against antigenically similar (84.3%; 95% CI: 70.1-92.4%) and any (64.2%; 95% CI: 44.2-77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite, and use of fever medication were more frequent with CAIV-T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV-T recipients. CONCLUSIONS: CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia.

Semiquantitative one-step RT-PCR for simultaneous identification of human influenza and respiratory syncytial viruses.

A multiplex reverse transcription-polymerase chain reaction (mRT-PCR) method was developed for simultaneous detection and typing/subtyping of influenza viruses A/H1, A/H3 or B, and respiratory syncytial viruses A or B, followed by DNA semiquantitation using the Agilent 2100 Bioanalyzer. Such method provides a rapid, specific and sensitive diagnostic tool for detection and semiquantification of respiratory illness specimens.

Improving the selection and development of influenza vaccine viruses - Report of a WHO informal consultation on improving influenza vaccine virus selection, Hong Kong SAR, China, 18-20 November 2015.

Since 2010 the WHO has held a series of informal consultations to explore ways of improving the currently highly complex and time-pressured influenza vaccine virus selection and development process. In November 2015 experts from around the world met to review the current status of efforts in this field. Discussion topics included strengthening influenza surveillance activities to increase the availability of candidate vaccine viruses and improve the extent, timeliness and quality of surveillance data. Consideration was also given to the development and potential application of newer laboratory assays to better characterize candidate vaccine viruses, the potential importance of antibodies directed against influenza virus neuraminidase, and the role of vaccine effectiveness studies. Advances in next generation sequencing and whole genome sequencing of influenza viruses were also discussed, along with associated developments in synthetic genomics technologies, evolutionary analysis and predictive mathematical modelling. Discussions were also held on the late emergence of an antigenic variant influenza A(H3N2) virus in mid-2014 that could not be incorporated in time into the 2014-15 northern hemisphere vaccine. There was broad recognition that given the current highly constrained influenza vaccine development and production timeline it would remain impossible to incorporate any variant virus which emerged significantly long after the relevant WHO biannual influenza vaccine composition meetings. Discussions were also held on the development of pandemic and broadly protective vaccines, and on associated regulatory and manufacturing requirements and constraints. With increasing awareness of the health and economic burdens caused by seasonal influenza, the ever-present threat posed by zoonotic influenza viruses, and the significant impact of the 2014-15 northern hemisphere seasonal influenza vaccine mismatch, this consultation provided a very timely opportunity to share developments and exchange views. In all areas, a renewed and strengthened emphasis was placed on developing concrete and measurable actions and identifying the key stakeholders responsible for their implementation.

Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome.

BACKGROUND: The worldwide outbreak of severe acute respiratory syndrome (SARS) is associated with a newly discovered coronavirus, SARS-associated coronavirus (SARS-CoV). We did clinical and experimental studies to assess the role of this virus in the cause of SARS. METHODS: We tested clinical and postmortem samples from 436 SARS patients in six countries for infection with SARS-CoV, human metapneumovirus, and other respiratory pathogens. We infected four cynomolgus macaques (Macaca fascicularis) with SARS-CoV in an attempt to replicate SARS and did necropsies on day 6 after infection. FINDINGS: SARS-CoV infection was diagnosed in 329 (75%) of 436 patients fitting the case definition of SARS; human metapneumovirus was diagnosed in 41 (12%) of 335, and other respiratory pathogens were diagnosed only sporadically. SARS-CoV was, therefore, the most likely causal agent of SARS. The four SARS-CoV-infected macaques excreted SARS-CoV from nose, mouth, and pharynx from 2 days after infection. Three of four macaques developed diffuse alveolar damage, similar to that in SARS patients, and characterised by epithelial necrosis, serosanguineous exudate, formation of hyaline membranes, type 2 pneumocyte hyperplasia, and the presence of syncytia. SARS-CoV was detected in pneumonic areas by virus isolation and RT-PCR, and was localised to alveolar epithelial cells and syncytia by immunohistochemistry and transmission electron microscopy. INTERPRETATION: Replication in SARS-CoV-infected macaques of pneumonia similar to that in human beings with SARS, combined with the high prevalence of SARS-CoV infection in SARS patients, fulfill the criteria required to prove that SARS-CoV is the primary cause of SARS.

Development of a real-time RT-PCR assay for detection and quantitation of parainfluenza virus 3.

A TaqMan-based real-time RT-PCR assay was developed to detect and quantify human parainfluenza virus 3 (PIV3). Two sets of primer-probe pairs were designed based on the nucleotide (nt) sequence of the nucleocapsid (N) gene. The primer-probe pairs were derived from the 3' end of the N gene (set 1) and the 5' region of the gene (set 2), respectively. Using real-time RT-PCR, the sensitivity of set 1 was determined to be about 9 copies of PIV3 genome, while the sensitivity of set 2 was about 93 copies of PIV3 genome. Set 1 was chosen for subsequent experiments. This primer-probe pair detected PIV3, but not any of several other respiratory viruses, indicating that the assay is PIV3 specific. For clinical evaluation, the assay was employed to test 80 nasopharyngeal aspirates from children with respiratory symptoms. The results confirmed the presence of PIV3 in 12 specimens previously identified as positive by culture confirmation, and showed all of which contained more than 100 copies of PIV3 genome. In addition, the method also detected PIV3 genomes in specimens found negative by culture confirmation, indicating the value of this RT-PCR assay. These data thus demonstrate the application of the real-time RT-PCR assay for the detection and quantification of PIV3 in clinical specimens.

The spectrum of severe acute respiratory syndrome-associated coronavirus infection.

BACKGROUND: Whether subclinical or atypical presentations of severe acute respiratory syndrome (SARS) occur and whether clinical judgment is accurate in detecting SARS are unknown. OBJECTIVES: To describe the spectrum of SARS coronavirus infection in a large outbreak and to compare diagnoses based on clinical judgment with the SARS coronavirus test. DESIGN: Secondary analysis of prospectively collected clinical data and archived serum. SETTING: A SARS screening clinic of a university hospital in the New Territories of Hong Kong. PATIENTS: 1221 patients attending the clinic between 12 March 2003 and 12 May 2003. MEASUREMENTS: SARS coronavirus serology. RESULTS: 145 of 553 (26%) patients had serologic evidence of SARS coronavirus infection. Of 910 patients who were managed without hospitalization, only 6 had serologic evidence of SARS. Five of the six patients had normal chest radiographs, and four had symptoms such as myalgia, chills, coughing, and feeling feverish. With the SARS coronavirus serologic test as the gold standard, the clinical diagnosis of probable SARS at hospitalization had a sensitivity of 0.96 (95% CI, 0.91 to 0.98) and a specificity of 0.96 (CI, 0.92 to 0.97). LIMITATIONS: Follow-up serologic samples were not obtained from almost half of the patients because they declined further testing. Some people living in the community who were infected but who had minor or no symptoms might not have visited the clinic. CONCLUSIONS: There is little evidence of widespread subclinical or mild forms of SARS coronavirus infection. Clinical diagnoses during the outbreak were reasonable and resulted in appropriate triaging.

The development of global vaccine stockpiles.

Global vaccine stockpiles, in which vaccines are reserved for use when needed for emergencies or supply shortages, have effectively provided countries with the capacity for rapid response to emergency situations, such as outbreaks of yellow fever and meningococcal meningitis. The high cost and insufficient supply of many vaccines, including oral cholera vaccine and pandemic influenza vaccine, have prompted discussion on expansion of the use of vaccine stockpiles to address a wider range of emerging and re-emerging diseases. However, the decision to establish and maintain a vaccine stockpile is complex and must take account of disease and vaccine characteristics, stockpile management, funding, and ethical concerns, such as equity. Past experience with global vaccine stockpiles provide valuable information about the processes for their establishment and maintenance. In this Review we explored existing literature and stockpile data to discuss the lessons learned and to inform the development of future vaccine stockpiles.

Seroprevalence of antibody to severe acute respiratory syndrome (SARS)-associated coronavirus among health care workers in SARS and non-SARS medical wards.

The seroprevalence of antibody to severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) in cohorts of health care workers (HCWs) with subclinical infection in SARS and non-SARS medical wards was 2.3% (3 of 131 HCWs) and 0% (0 of 192 HCWs), respectively. Rates for clinical SARS-CoV infection among 742 HCWs on these wards were highest among nurses (11.6%) and health care assistants (11.8%), indicating that these occupations are associated with the highest risks for exposure.

Incidence of rotavirus diarrhea and intussusception in Hong Kong using standardized hospital discharge data.

Incidence for rotavirus and intussusception was estimated from standardized discharge data for all Hong Kong government hospitals (1997 to 1999). Intussusception incidence in infants (78 to 100 of 100,000) was relatively high. The distinct winter seasonality of rotavirus was not evident for intussusception. During the first 5 years of life an estimated 1 child of 28 is admitted with rotavirus infection (4% of all medical admissions).

Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients.

BACKGROUND: The effect of corticosteroid treatment on the viral load of Severe Acute Respiratory Syndrome (SARS) patients is unknown. OBJECTIVE: To compare the plasma SARS-CoV RNA concentrations in ribavirin-treated patients who received early hydrocortisone therapy with those who received placebo. STUDY DESIGN: Serial plasma SARS-CoV RNA concentrations measured in the setting of a prospective, randomized double-blinded, placebo-controlled trial designed to assess the efficacy of "early" (<7 days of illness) hydrocortisone use in previously healthy SARS patients were analyzed. SARS-CoV RNA was quantified using a one-step real-time RT-PCR assay targeting the nucleocapsid gene. RESULTS: Among 16 non-ICU cases, SARS-CoV RNA was detected in plasma since day 3-4 after fever onset; viral concentration peaked in the first week, which then rapidly declined in the second week of illness. On days 8, 12, 16, and 20, the cumulative proportion of patients with undetectable virus in plasma was 31%, 69%, 92%, and 100%, respectively. Plasma SARS-CoV RNA concentrations in the second and third week of illness were significantly higher in patients who received initial hydrocortisone treatment (n = 9), as compared to those who received placebo (n = 7)(AUC; Mann-Whitney, P = 0.023). The median time for SARS-CoV to become undetectable in plasma was 12 days (11-20 days) versus 8 days (8-15 days), respectively. CONCLUSION: Our findings suggested "early" corticosteroid treatment was associated with a higher subsequent plasma viral load.

International meeting on influenza vaccine effectiveness, 3-4 December 2012, Geneva, Switzerland.

On December 3­4 2012, the World Health Organization convened a meeting of influenza vaccine effectiveness (VE) experts from over 25 countries in Geneva, Switzerland, to review recent developments in the global influenza vaccine landscape and evaluate approaches to determining the effectiveness of influenza vaccine products among target populations. Vaccine manufacturers from Thailand, Vietnam, India, and Brazil shared recent advances illustrating the expansion of influenza vaccine production worldwide. Randomized controlled trials are underway in several low and middle-income countries including India, Thailand, Bangladesh, and South Africa, to fill knowledge gaps in target populations such as children and pregnant women. National and international networks in the United States, Canada, Europe, Latin America and Australia are conducting multi-site observational studies with shared methodologies to generate national influenza VE estimates and pool data for regional estimates. Standardized VE estimation methods are key to generating point estimates that are comparable internationally and across different settings.

Burden of influenza infection in hospitalised children below 6 months of age and above in Hong Kong from 2005 to 2011.

The World Health Organization recommends vaccination of pregnant women for seasonal influenza that can also protect infants aged below 6 months. We estimated incidence and disease burden of influenza in hospitalised children below and above 6 months of age in Hong Kong during a 6 year period. Discharge diagnoses for all admissions to public Hong Kong Hospital Authority hospitals, recorded in a central computerised database (Clinical Management System, CMS), were analysed for the period April 2005 to March 2011. Incidence estimates of influenza disease by age group were derived from CMS ICD codes 487-487.99. Laboratory-confirmed influenza infections from a single surveillance hospital were then linked to the CMS entries to assess possible over- and under-diagnosis of influenza based on CMS codes alone. Influenza was recorded as any primary or any secondary diagnosis in 1.3% (1158/86,582) of infants aged above 6 days to below 6 months and 4.3% (20,230/471,482) of children above 6 days to below 18 years. The unadjusted incidence rates per 100,000 person-years based on any CMS diagnosis of influenza in all admission to Hong Kong public hospitals were 627 in the below 2 months of age group and 1762 in the 2 month to below 6 month group. Incidence of hospitalisation for influenza in children was highest from 2 months to below 6 months. In the absence of vaccines for children below 6 months of age, effective vaccination of pregnant women may have a significant impact on reducing influenza hospitalisations in this age group.

Report on the first WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses: Hong Kong SAR, China, 24-26 January 2013.

On January 24-26, 2013, the World Health Organization convened the first integrated meeting on "The development and clinical trials of vaccines that induce broadly protective and long-lasting immune responses" to review the current status of development and clinical evaluation of novel influenza vaccines as well as strategies to produce and deliver vaccines in novel ways. Special attention was given to the development of possible universal influenza vaccines. Other topics that were addressed included an update on clinical trials of pandemic and seasonal influenza vaccines in high-risk groups and vaccine safety, as well as regulatory issues.

Overview of Influenza Vaccines in Children.

Prevention of influenza infection through vaccination is the best strategy to reduce its disease burden; however, annual revaccination is required to provide protection from circulating virus strains. Currently available influenza vaccines are trivalent inactivated influenza vaccines (IIV) or live-attenuated influenza vaccines (LAIV); however, quadrivalent formulations of IIV and LAIV are expected to be available for the 2013-2014 influenza season. Among children 6 months through 8 years of age receiving their first influenza vaccination, 2 doses of vaccines are required to provide adequate protection. Because of the wide range of circulating influenza viruses and host immune responses, estimates of vaccine effectiveness vary widely by year, age group, and vaccine studied. We summarize the evidence base for pediatric influenza vaccination, and we describe the challenges and limitations of protecting this population with currently available vaccines.

Efficacy and effectiveness of seasonal and pandemic A (H1N1) 2009 influenza vaccines in low and middle income countries: a systematic review and meta-analysis.

PURPOSE: Influenza vaccines have been recommended for populations at risk for severe infection in low and middle income countries (LMICs) although knowledge of the evidence-base for their effectiveness and efficacy is limited in these countries. The aim of this systematic review is to provide an overview of the evidence-base for the effectiveness and efficacy of influenza vaccines in LMICs and to explore critical knowledge gaps. METHODS: PubMed, EMBASE, and Cochrane were searched for seasonal and pandemic A (H1N1) 2009 influenza vaccine effectiveness and efficacy studies performed in LMICs. Eligible studies included RCTs and observational studies, published in English, French, Spanish or Portuguese between 1960 and 2011, which assessed laboratory-confirmed influenza and/or influenza-related outcomes in any population. Risk of bias was assessed by two reviewers independently. Random effects pooled estimates were obtained when sufficient data were available. RESULTS: A total of 6465 articles were screened. Forty-one studies were included on seasonal influenza vaccine effectiveness and efficacy and one study on pandemic vaccine effectiveness. In middle income countries (MICs), efficacy of seasonal influenza vaccines was shown against laboratory-confirmed influenza in children (pooled efficacy 72% (95%CI: 65-77) and 81% (95%CI: 69-89), for one and two years follow-up respectively) and in the elderly (pooled efficacy 43% (95%CI: 25-56) and 58% (95%CI: 23-78), for live attenuated and inactivated vaccine respectively). Inactivated influenza vaccines were also found to be effective against cardiovascular outcomes in patients with coronary syndromes. CONCLUSIONS: Seasonal influenza vaccines can provide protection in children, the elderly and patients with coronary syndromes in MICs, and seem to be equally effective as compared to high income countries. Data for other high risk groups and from low income countries were limited or prone to bias, and are needed to further facilitate evidence-based decision making regarding influenza vaccination in LMICs.