Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology.

Evidence suggests that innate and adaptive cellular responses mediate resistance to the influenza virus and confer protection after vaccination. However, few studies have resolved the contribution of cellular responses within the context of preexisting antibody titers. Here, we measured the peripheral immune profiles of 206 vaccinated or unvaccinated adults to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza. Protection correlated with diverse and polyfunctional CD4+ and CD8+ T, circulating T follicular helper, T helper type 17, myeloid dendritic and CD16+ natural killer (NK) cell subsets. Conversely, increased susceptibility was predominantly attributed to nonspecific inflammatory populations, including γδ T cells and activated CD16- NK cells, as well as TNFα+ single-cytokine-producing CD8+ T cells. Multivariate and predictive modeling indicated that cellular subsets (1) work synergistically with humoral immunity to confer protection, (2) improve model performance over demographic and serologic factors alone and (3) comprise the most important predictive covariates. Together, these results demonstrate that preinfection peripheral cell composition improves the prediction of symptomatic influenza susceptibility over vaccination, demographics or serology alone.

The burden of HMPV and influenza associated hospitalizations in adults in New Zealand, 2012-2015.

BACKGROUND: Unlike influenza, information on the burden of human metapneumovirus (HMPV) as a cause of hospitalizations in adults with acute respiratory illness (ARI) is limited. METHODS: We compared the population-based incidence, seasonality, and clinical characteristics of these two viral infections among adults aged 20 years and over with ARI hospitalisations in Auckland, New Zealand, during 2012-2015 through the Southern Hemisphere Influenza Vaccine Effectiveness Research and Surveillance (SHIVERS) project. RESULTS: Of the 14,139 ARI hospitalisations, 276 (4.3%) of 6484 tested positive for HMPV and 1342 (19.1%) of 7027 tested positive for influenza. Crude rates of 9.8 (95% CI: 8.7-11.0) HMPV and 47.6 (95% CI: 45.1-50.1) influenza-associated ARI hospitalisations were estimated for every 100,000 adult residents annually. The highest rates for both viruses were in those aged 80 years or older, of Maori or Pacific ethnicity, or living in low socioeconomic status (SES) areas. HMPV infections were more common than influenza in those with chronic medical conditions. CONCLUSIONS: Although HMPV infections accounted for fewer hospitalisations than influenza in adults aged 20 years and over, HMPV-associated ARI hospitalisation rates were higher than influenza in older adults, Maori and Pacific people and those of low SES. This highlighted a need for vaccine/antiviral development.

Use of Genomics to Track Coronavirus Disease Outbreaks, New Zealand.

Real-time genomic sequencing has played a major role in tracking the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), contributing greatly to disease mitigation strategies. In August 2020, after having eliminated the virus, New Zealand experienced a second outbreak. During that outbreak, New Zealand used genomic sequencing in a primary role, leading to a second elimination of the virus. We generated genomes from 78% of the laboratory-confirmed samples of SARS-CoV-2 from the second outbreak and compared them with the available global genomic data. Genomic sequencing rapidly identified that virus causing the second outbreak in New Zealand belonged to a single cluster, thus resulting from a single introduction. However, successful identification of the origin of this outbreak was impeded by substantial biases and gaps in global sequencing data. Access to a broader and more heterogenous sample of global genomic data would strengthen efforts to locate the source of any new outbreaks.

Genomic Evidence of In-Flight Transmission of SARS-CoV-2 Despite Predeparture Testing.

Since the first wave of coronavirus disease in March 2020, citizens and permanent residents returning to New Zealand have been required to undergo managed isolation and quarantine (MIQ) for 14 days and mandatory testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of October 20, 2020, of 62,698 arrivals, testing of persons in MIQ had identified 215 cases of SARS-CoV-2 infection. Among 86 passengers on a flight from Dubai, United Arab Emirates, that arrived in New Zealand on September 29, test results were positive for 7 persons in MIQ. These passengers originated from 5 different countries before a layover in Dubai; 5 had negative predeparture SARS-CoV-2 test results. To assess possible points of infection, we analyzed information about their journeys, disease progression, and virus genomic data. All 7 SARS-CoV-2 genomes were genetically identical, except for a single mutation in 1 sample. Despite predeparture testing, multiple instances of in-flight SARS-CoV-2 transmission are likely.

Risk Factors and Attack Rates of Seasonal Influenza Infection: Results of the Southern Hemisphere Influenza and Vaccine Effectiveness Research and Surveillance (SHIVERS) Seroepidemiologic Cohort Study.

Background: Understanding the attack rate of influenza infection and the proportion who become ill by risk group is key to implementing prevention measures. While population-based studies of antihemagglutinin antibody responses have been described previously, studies examining both antihemagglutinin and antineuraminidase antibodies are lacking. Methods: In 2015, we conducted a seroepidemiologic cohort study of individuals randomly selected from a population in New Zealand. We tested paired sera for hemagglutination inhibition (HAI) or neuraminidase inhibition (NAI) titers for seroconversion. We followed participants weekly and performed influenza polymerase chain reaction (PCR) for those reporting influenza-like illness (ILI). Results: Influenza infection (either HAI or NAI seroconversion) was found in 321 (35% [95% confidence interval, 32%-38%]) of 911 unvaccinated participants, of whom 100 (31%) seroconverted to NAI alone. Young children and Pacific peoples experienced the highest influenza infection attack rates, but overall only a quarter of all infected reported influenza PCR-confirmed ILI, and one-quarter of these sought medical attention. Seroconversion to NAI alone was higher among children aged <5 years vs those aged ≥5 years (14% vs 4%; P < .001) and among those with influenza B vs A(H3N2) virus infections (7% vs 0.3%; P < .001). Conclusions: Measurement of antineuraminidase antibodies in addition to antihemagglutinin antibodies may be important in capturing the true influenza infection rates.

Heterogeneity in influenza seasonality and vaccine effectiveness in Australia, Chile, New Zealand and South Africa: early estimates of the 2019 influenza season.

We compared 2019 influenza seasonality and vaccine effectiveness (VE) in four southern hemisphere countries: Australia, Chile, New Zealand and South Africa. Influenza seasons differed in timing, duration, intensity and predominant circulating viruses. VE estimates were also heterogeneous, with all-ages point estimates ranging from 7-70% (I2: 33%) for A(H1N1)pdm09, 4-57% (I2: 49%) for A(H3N2) and 29-66% (I2: 0%) for B. Caution should be applied when attempting to use southern hemisphere data to predict the northern hemisphere influenza season.

Influenza vaccine effectiveness during the 2012 influenza season in Victoria, Australia: influences of waning immunity and vaccine match.

Vaccine effectiveness may wane with increasing time since vaccination. This analysis used the Victorian sentinel general practitioner (GP) network to estimate vaccine effectiveness for trivalent inactivated vaccines in the 2012 season. A test-negative design was used where patients presenting to GPs with influenza-like illness who tested positive for influenza were cases and noncases were those who tested negative. Vaccination status was recorded by GPs. Vaccine effectiveness was calculated as (1-odds ratio) × 100%. Estimates were compared early versus late in the season and by time since vaccination. Virus isolates were assessed antigenically by hemagglutination inhibition assay in a selection of positive samples and viruses from healthy adults who experienced a vaccine breakthrough were analyzed genetically. The adjusted vaccine effectiveness estimate for any type of influenza was 45% (95% CI: 8,66) and for influenza A(H3) was 35% (95% CI: -11,62). A non-significant effect of waning effectiveness by time since vaccination was observed for A(H3). For those vaccinated <93 days of presentation vaccine effectiveness was 37% (95% CI: -29,69), while for those vaccinated ≥93 days before presentation it was 18% (95% CI: -83,63). Comparison of early versus late in the season estimates was very sensitive to the cut off week chosen for analysis. Antigenic data suggested that low vaccine effectiveness was not associated with poor vaccine match among the A(H3) viruses. However, genetic analysis suggested nucleotide substitutions in antigenic sites. In 2012, the trivalent influenza vaccine provided moderate protection against influenza and showed limited evidence for waning effectiveness. Antigenic and genetic data can provide additional insight into understanding these estimates.

Impact of the COVID-19 related border restrictions on influenza and other common respiratory viral infections in New Zealand.

BACKGROUND: New Zealand's (NZ) complete absence of community transmission of influenza and respiratory syncytial virus (RSV) after May 2020, likely due to COVID-19 elimination measures, provided a rare opportunity to assess the impact of border restrictions on common respiratory viral infections over the ensuing 2 years. METHODS: We collected the data from multiple surveillance systems, including hospital-based severe acute respiratory infection surveillance, SHIVERS-II, -III and -IV community cohorts for acute respiratory infection (ARI) surveillance, HealthStat sentinel general practice (GP) based influenza-like illness surveillance and SHIVERS-V sentinel GP-based ARI surveillance, SHIVERS-V traveller ARI surveillance and laboratory-based surveillance. We described the data on influenza, RSV and other respiratory viral infections in NZ before, during and after various stages of the COVID related border restrictions. RESULTS: We observed that border closure to most people, and mandatory government-managed isolation and quarantine on arrival for those allowed to enter, appeared to be effective in keeping influenza and RSV infections out of the NZ community. Border restrictions did not affect community transmission of other respiratory viruses such as rhinovirus and parainfluenza virus type-1. Partial border relaxations through quarantine-free travel with Australia and other countries were quickly followed by importation of RSV in 2021 and influenza in 2022. CONCLUSION: Our findings inform future pandemic preparedness and strategies to model and manage the impact of influenza and other respiratory viral threats.

Circulation of influenza and other respiratory viruses during the COVID-19 pandemic in Australia and New Zealand, 2020-2021.

Objective: Circulation patterns of influenza and other respiratory viruses have been globally disrupted since the emergence of coronavirus disease (COVID-19) and the introduction of public health and social measures (PHSMs) aimed at reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Methods: We reviewed respiratory virus laboratory data, Google mobility data and PHSMs in five geographically diverse regions in Australia and New Zealand. We also described respiratory virus activity from January 2017 to August 2021. Results: We observed a change in the prevalence of circulating respiratory viruses following the emergence of SARS-CoV-2 in early 2020. Influenza activity levels were very low in all regions, lower than those recorded in 2017-2019, with less than 1% of laboratory samples testing positive for influenza virus. In contrast, rates of human rhinovirus infection were increased. Respiratory syncytial virus (RSV) activity was delayed; however, once it returned, most regions experienced activity levels well above those seen in 2017-2019. The timing of the resurgence in the circulation of both rhinovirus and RSV differed within and between the two countries. Discussion: The findings of this study suggest that as domestic and international borders are opened up and other COVID-19 PHSMs are lifted, clinicians and public health professionals should be prepared for resurgences in influenza and other respiratory viruses. Recent patterns in RSV activity suggest that these resurgences in non-COVID-19 viruses have the potential to occur out of season and with increased impact.

Genomic epidemiology of Delta SARS-CoV-2 during transition from elimination to suppression in Aotearoa New Zealand.

New Zealand's COVID-19 elimination strategy heavily relied on the use of genomics to inform contact tracing, linking cases to the border and to clusters during community outbreaks. In August 2021, New Zealand entered its second nationwide lockdown after the detection of a single community case with no immediately apparent epidemiological link to the border. This incursion resulted in the largest outbreak seen in New Zealand caused by the Delta Variant of Concern. Here we generated 3806 high quality SARS-CoV-2 genomes from cases reported in New Zealand between 17 August and 1 December 2021, representing 43% of reported cases. We detected wide geographical spread coupled with undetected community transmission, characterised by the apparent extinction and reappearance of genomically linked clusters. We also identified the emergence, and near replacement, of genomes possessing a 10-nucleotide frameshift deletion that caused the likely truncation of accessory protein ORF7a. By early October, New Zealand moved from an elimination strategy to a suppression strategy and the role of genomics changed markedly from being used to track and trace, towards population-level surveillance.

Activated CD4+ T cells and CD14hiCD16+ monocytes correlate with antibody response following influenza virus infection in humans.

The failure to mount an antibody response following viral infection or seroconversion failure is a largely underappreciated and poorly understood phenomenon. Here, we identified immunologic markers associated with robust antibody responses after influenza virus infection in two independent human cohorts, SHIVERS and FLU09, based in Auckland, New Zealand and Memphis, Tennessee, USA, respectively. In the SHIVERS cohort, seroconversion significantly associates with (1) hospitalization, (2) greater numbers of proliferating, activated CD4+ T cells, but not CD8+ T cells, in the periphery during the acute phase of illness, and (3) fewer inflammatory monocytes (CD14hiCD16+) by convalescence. In the FLU09 cohort, fewer CD14hiCD16+ monocytes during early illness in the nasal mucosa were also associated with the generation of influenza-specific mucosal immunoglobulin A (IgA) and IgG antibodies. Our study demonstrates that seroconversion failure after infection is a definable immunological phenomenon, associated with quantifiable cellular markers that can be used to improve diagnostics, vaccine efficacy, and epidemiologic efforts.

Uncoupling Molecular Testing for SARS-CoV-2 From International Supply Chains.

The rapid global rise of COVID-19 from late 2019 caught major manufacturers of RT-qPCR reagents by surprise and threw into sharp focus the heavy reliance of molecular diagnostic providers on a handful of reagent suppliers. In addition, lockdown and transport bans, necessarily imposed to contain disease spread, put pressure on global supply lines with freight volumes severely restricted. These issues were acutely felt in New Zealand, an island nation located at the end of most supply lines. This led New Zealand scientists to pose the hypothetical question: in a doomsday scenario where access to COVID-19 RT-qPCR reagents became unavailable, would New Zealand possess the expertise and infrastructure to make its own reagents onshore? In this work we describe a review of New Zealand's COVID-19 test requirements, bring together local experts and resources to make all reagents for the RT-qPCR process, and create a COVID-19 diagnostic assay referred to as HomeBrew (HB) RT-qPCR from onshore synthesized components. This one-step RT-qPCR assay was evaluated using clinical samples and shown to be comparable to a commercial COVID-19 assay. Through this work we show New Zealand has both the expertise and, with sufficient lead time and forward planning, infrastructure capacity to meet reagent supply challenges if they were ever to emerge.

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand.

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020. This finding supports the use of these NPIs for controlling pandemic influenza and other severe respiratory viral threats.

The health and economic burden of respiratory syncytial virus associated hospitalizations in adults.

BACKGROUND: Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of illness in adults; however, data on RSV disease and economic burden in this age group remain limited. We aimed to provide comprehensive estimates of RSV disease burden among adults aged ≥18 years. METHODS: During 2012-2015, population-based, active surveillance of acute respiratory infection (ARI) hospitalizations enabled estimation of the seasonal incidence of RSV hospitalizations and direct health costs in adults aged ≥18 years in Auckland, New Zealand. RESULTS: Of 4,600 ARI hospitalizations tested for RSV, 348 (7.6%) were RSV positive. The median (interquartile range) length of hospital stay for RSV positive patients was 4 (2-6) days. The seasonal incidence rate (IR) of RSV hospitalizations, corrected for non-testing, was 23.6 (95% confidence intervals [CI] 21.0-26.1) per 100,000 adults aged ≥18 years. Hospitalization risk increased with age with the highest incidence among adults aged ≥80 years (IR 190.8 per 100,000, 95% CI 137.6-244.0). Being of Maori or Pacific ethnicity or living in a neighborhood with low socioeconomic status (SES) were independently associated with increased RSV hospitalization rates. We estimate RSV-associated hospitalizations among adults aged ≥18 years to cost on average NZD $4,758 per event. CONCLUSIONS: RSV infection is associated with considerable disease and economic cost in adults. RSV disproportionally affects adult sub-groups defined by age, ethnicity, and neighborhood SES. An effective RSV vaccine or RSV treatment may offer benefits for older adults.

Genomic epidemiology reveals transmission patterns and dynamics of SARS-CoV-2 in Aotearoa New Zealand.

New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nationwide 'lockdown' of all non-essential services to curb the spread of COVID-19. Here, we generate 649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected during the 'first wave', representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. These data helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, Re of New Zealand's largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in ongoing transmission of more than one additional case. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand.

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020. This finding supports the use of these NPIs for controlling pandemic influenza and other severe respiratory viral threats.

Erratum: Pyke, A.T. et al. On the Home Front: Specialized Reference Testing for Dengue in the Australasian Region. Trop. Med. Infect. Dis. 2018, 3, 75.

The authors wish to make the following correction to Table 1 of this paper [...].

On the Home Front: Specialised Reference Testing for Dengue in the Australasian Region.

Reference laboratories are vital for disease control and interpreting the complexities and impact of emerging pathogens. The role of these centralized facilities extends beyond routine screening capabilities to provide rapid, specific, and accurate diagnoses, advanced data analysis, consultation services, and sophisticated disease surveillance and monitoring. Within the Australasian region, the Public Health Virology Laboratory (PHV), Forensic and Scientific Services, Department of Health, Queensland Government, Australia, and the Institute of Environmental Science and Research Limited (ESR), New Zealand (NZ) perform specialised reference testing and surveillance for dengue viruses (DENVs) and other emerging arthropod-borne viruses (arboviruses), including chikungunya virus (CHIKV) and Zika virus (ZIKV). With a focus on DENV, we review the reference testing performed by PHV (2005 to 2017) and ESR (2008 to 2017). We also describe how the evolution and expansion of reference-based methodologies and the adoption of new technologies have provided the critical elements of preparedness and early detection that complement frontline public health control efforts and limit the spread of arboviruses within Australasia.

Influenza C infections in Western Australia and Victoria from 2008 to 2014.

BACKGROUND: Influenza C is usually considered a minor cause of respiratory illness in humans with many infections being asymptomatic or clinically mild. Large outbreaks can occur periodically resulting in significant morbidity. OBJECTIVES: This study aimed at analyzing the available influenza C clinical samples from two widely separated states of Australia, collected over a 7-year period and to compare them with influenza C viruses detected in other parts of the world in recent years. PATIENTS/METHODS: Between 2008 and 2014, 86 respiratory samples that were influenza C positive were collected from subjects with influenza-like illness living in the states of Victoria and Western Australia. A battery of other respiratory viruses were also tested for in these influenza C-positive samples. Virus isolation was attempted on all of these clinical samples, and gene sequencing was performed on all influenza C-positive cultures. RESULTS AND CONCLUSIONS: Detections of influenza C in respiratory samples were sporadic in most years studied, but higher rates of infection occurred in 2012 and 2014. Many of the patients with influenza C had coinfections with other respiratory pathogens. Phylogenetic analysis of the full-length hemagglutinin-esterase-fusion (HE) gene found that most of the viruses grouped in the C/Sao Paulo/378/82 clade with the remainder grouping in the C/Kanagawa/1/76 clade.

A simplified Sanger sequencing method for full genome sequencing of multiple subtypes of human influenza A viruses.

BACKGROUND: Full genome sequencing of influenza A viruses (IAV), including those that arise from annual influenza epidemics, is undertaken to determine if reassorting has occurred or if other pathogenic traits are present. Traditionally IAV sequencing has been biased toward the major surface glycoproteins haemagglutinin and neuraminidase, while the internal genes are often ignored. Despite the development of next generation sequencing (NGS), many laboratories are still reliant on conventional Sanger sequencing to sequence IAV. OBJECTIVES: To develop a minimal and robust set of primers for Sanger sequencing of the full genome of IAV currently circulating in humans. STUDY DESIGN: A set of 13 primer pairs was designed that enabled amplification of the six internal genes of multiple human IAV subtypes including the recent avian influenza A(H7N9) virus from China. Specific primers were designed to amplify the HA and NA genes of each IAV subtype of interest. Each of the primers also incorporated a binding site at its 5'-end for either a forward or reverse M13 primer, such that only two M13 primers were required for all subsequent sequencing reactions. RESULTS: This minimal set of primers was suitable for sequencing the six internal genes of all currently circulating human seasonal influenza A subtypes as well as the avian A(H7N9) viruses that have infected humans in China. CONCLUSIONS: This streamlined Sanger sequencing protocol could be used to generate full genome sequence data more rapidly and easily than existing influenza genome sequencing protocols.