Antigenic drift and immunity gap explain reduction in protective responses against influenza A(H1N1)pdm09 and A(H3N2) viruses during the COVID-19 pandemic: a cross-sectional study of human sera collected in 2019, 2021, 2022, and 2023.

BACKGROUND: Non-pharmaceutical interventions implemented during the COVID-19 pandemic resulted in a marked reduction in influenza infections globally. The absence of influenza has raised concerns of waning immunity, and potentially more severe influenza seasons after the pandemic. METHODS: To evaluate immunity towards influenza post-COVID-19 pandemic we have assessed influenza A epidemics in Norway from October 2016 to June 2023 and measured antibodies against circulating strains of influenza A(H1N1)pdm09 and A(H3N2) in different age groups by hemagglutination inhibition (HAI) assays in a total of 3364 serum samples collected in 2019, 2021, 2022 and 2023. RESULTS: Influenza epidemics in Norway from October 2016 until June 2023 were predominately influenza As, with a mixture of A(H1N1)pdm09 and A(H3N2) subtype predominance. We did not observe higher numbers of infections during the influenza epidemics following the COVID-19 pandemic than in pre-COVID-19 seasons. Frequencies of protective HAI titers against A(H1N1)pdm09 and A(H3N2) viruses were reduced in sera collected in 2021 and 2022, compared to sera collected in 2019. The reduction could, however, largely be explained by antigenic drift of new virus strains, as protective HAI titers remained stable against the same strain from one season to the next. However, we observed the development of an immunity gap in the youngest children during the pandemic which resulted in a prominent reduction in HAI titers against A(H1N1)pdm09 in 2021 and 2022. The immunity gap was partially closed in sera collected in 2023 following the A(H1N1)pdm09-dominated influenza seasons of 2022/2023. During the 2022/2023 epidemic, drift variants of A(H1N1)pdm09 belonging to the 5a.2a.1 clade emerged, and pre-season HAI titers were significantly lower against this clade compared to the ancestral 5a.2 clade. CONCLUSION: The observed reduction in protective antibodies against A(H1N1)pdm09 and A(H3N2) viruses post COVID-19 is best explained by antigenic drift of emerging viruses, and not waning of antibody responses in the general population. However, the absence of influenza during the pandemic resulted in an immunity gap in the youngest children. While this immunity gap was partially closed following the 2022/2023 influenza season, children with elevated risk of severe infection should be prioritized for vaccination.

Evaluation of the pilot wastewater surveillance for SARS-CoV-2 in Norway, June 2022 - March 2023.

BACKGROUND: During the COVID-19 pandemic, wastewater-based surveillance gained great international interest as an additional tool to monitor SARS-CoV-2. In autumn 2021, the Norwegian Institute of Public Health decided to pilot a national wastewater surveillance (WWS) system for SARS-CoV-2 and its variants between June 2022 and March 2023. We evaluated the system to assess if it met its objectives and its attribute-based performance. METHODS: We adapted the available guidelines for evaluation of surveillance systems. The evaluation was carried out as a descriptive analysis and consisted of the following three steps: (i) description of the WWS system, (ii) identification of users and stakeholders, and (iii) analysis of the system's attributes and performance including sensitivity, specificity, timeliness, usefulness, representativeness, simplicity, flexibility, stability, and communication. Cross-correlation analysis was performed to assess the system's ability to provide early warning signal of new wave of infections. RESULTS: The pilot WWS system was a national surveillance system using existing wastewater infrastructures from the largest Norwegian municipalities. We found that the system was sensitive, timely, useful, representative, simple, flexible, acceptable, and stable to follow the general trend of infection. Preliminary results indicate that the system could provide an early signal of changes in variant distribution. However, challenges may arise with: (i) specificity due to temporary fluctuations of RNA levels in wastewater, (ii) representativeness when downscaling, and (iii) flexibility and acceptability when upscaling the system due to limited resources and/or capacity. CONCLUSIONS: Our results showed that the pilot WWS system met most of its surveillance objectives. The system was able to provide an early warning signal of 1-2 weeks, and the system was useful to monitor infections at population level and complement routine surveillance when individual testing activity was low. However, temporary fluctuations of WWS values need to be carefully interpreted. To improve quality and efficiency, we recommend to standardise and validate methods for assessing trends of new waves of infection and variants, evaluate the WWS system using a longer operational period particularly for new variants, and conduct prevalence studies in the population to calibrate the system and improve data interpretation.

Covid-19 and influenza vaccine effectiveness against associated hospital admission and death among individuals over 65 years in Norway: A population-based cohort study, 3 October 2022 to 20 June 2023.

BACKGROUND: Co-circulation of SARS-CoV-2 and influenza virus can lead to double epidemics and increased pressure on health systems. To evaluate the effect of both vaccines, we estimated the adjusted vaccine effectiveness (aVE) of influenza and Covid-19 vaccines against related severe disease in the elderly population in Norway during the 2022/2023 season. METHODS: In this population-based cohort study, we included data from the Emergency preparedness register for Covid-19 (Beredt C19) on all individuals ≥ 65 years living in Norway between 3 October 2022 and 20 June 2023. Using Cox-proportional hazard models, we estimated aVE of both influenza and Covid-19 vaccines (bivalent BA.1 and BA.4-5) against associated hospitalisation and death. Vaccine status was included as a time-varying covariate and all models were adjusted for potential confounders, including the other vaccine. RESULTS: We identified 2,437 influenza-associated hospitalisations and 178 deaths, alongside 5,824 Covid-19-associated hospitalisations and 621 deaths. The aVE was highest in the first three months after receiving either vaccine. Against influenza-associated hospitalisation the aVE was 34 % (26 %-42 %) among 65-79-year-olds and 40 % (30 %-48 %) among ≥ 80-year-olds, and 6.6 % (-64 %-47 %) and 37 % (0.5 %-61 %) against influenza-associated death, respectively. The aVE against Covid-19-associated hospitalisation was 65 % (61 %-69 %) among 65-79-year-olds and 55 % (49 %-60 %) among ≥ 80-year-olds (compared to having received the vaccine ≥ 180 days ago). Similarly, the aVE against Covid-19-associated death was 68 % (48 %-80 %) and 78 % (65 %-86 %), respectively. For Covid-19 we show a reduction in aVE with time since dose. CONCLUSION: Covid-19 and influenza vaccines reduced the risk of severe disease in the same high-risk population. Ensuring high uptake of both vaccines could thus limit the overall health care burden.

Novel Reassortant H5N6 Influenza A Virus from the Lao People's Democratic Republic Is Highly Pathogenic in Chickens.

Avian influenza viruses of H5 subtype can cause highly pathogenic disease in poultry. In March 2014, a new reassortant H5N6 subtype highly pathogenic avian influenza virus emerged in Lao People's Democratic Republic. We have assessed the pathogenicity, pathobiology and immunological responses associated with this virus in chickens. Infection caused moderate to advanced disease in 6 of 6 chickens within 48 h of mucosal inoculation. High virus titers were observed in blood and tissues (kidney, spleen, liver, duodenum, heart, brain and lung) taken at euthanasia. Viral antigen was detected in endothelium, neurons, myocardium, lymphoid tissues and other cell types. Pro-inflammatory cytokines were elevated compared to non-infected birds. Our study confirmed that this new H5N6 reassortant is highly pathogenic, causing disease in chickens similar to that of Asian H5N1 viruses, and demonstrated the ability of such clade 2.3.4-origin H5 viruses to reassort with non-N1 subtype viruses while maintaining a fit and infectious phenotype. Recent detection of influenza H5N6 poultry infections in Lao PDR, China and Viet Nam, as well as six fatal human infections in China, demonstrate that these emergent highly pathogenic H5N6 viruses may be widely established in several countries and represent an emerging threat to poultry and human populations.

Characterisation of chicken viperin.

The identification of immune pathways that protect against pathogens may lead to novel molecular therapies for both livestock and human health. Interferon (IFN) is a major response pathway that stimulates multiple genes targeted towards reducing virus. Viperin is one such interferon stimulated gene (ISG) that helps protect mammals from virus and may be critical to protecting chickens in the same way. In chickens, ISGs are not generally well characterised and viperin, in concert with other ISGs, may be important in protecting against virus. Here we identify chicken viperin (ch-viperin) and show that ch-viperin is upregulated in response to viral signature molecules. We further show that viperin is upregulated in response to virus infection in vivo. This data will benefit investigators targeting the antiviral pathways in the chicken.