Minami Nagai et al.
High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection
Nature, June 2023; doi.org/10.1038/s41467-023-39569-0
Abstract
Fever is a common symptom of influenza and coronavirus disease 2019 (COVID-19), yet its physiological role in host resistance to viral infection remains less clear. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C increases host resistance to viral pathogens including influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High heat-exposed mice increase basal body temperature over 38 °C to enable more bile acids production in a gut microbiota-dependent manner. The gut microbiota-derived deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G-protein-coupled receptor 5 (TGR5) signaling increase host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage. Furthermore, the DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamsters from lethal SARS-CoV-2 infection. Moreover, we demonstrate that certain bile acids are reduced in the plasma of COVID-19 patients who develop moderate I/II disease compared with the minor severity of illness group. These findings implicate a mechanism by which virus-induced high fever increases host resistance to influenza virus and SARS-CoV-2 in a gut microbiota-dependent manner.
Zhenzhen Wang et al.
A SARS-CoV-2 and influenza double hit vaccine based on RBD-conjugated inactivated influenza A virus
Science, June 2023; doi/10.1126/sciadv.abo4100
Abstract
The circulating flu viruses merging with the ongoing COVID-19 pandemic raises a more severe threat that promotes the infectivity of SARS-CoV-2 associated with higher mortality rates. Here, we conjugated recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein onto inactivated influenza A virus (Flu) to develop a SARS-CoV-2 virus-like particle (VLP) vaccine with two-hit protection. This double-hit vaccine (Flu-RBD) not only induced protective immunities against SARS-CoV-2 but also remained functional as a flu vaccine. The Flu core improved the retention and distribution of Flu-RBD vaccine in the draining lymph nodes, with enhanced immunogenicity. In a hamster model of live SARS-CoV-2 infection, two doses of Flu-RBD efficiently protected animals against viral infection. Furthermore, Flu-RBD VLP elicited a strong neutralization activity against both SARS-CoV-2 Delta pseudovirus and wild-type influenza A H1N1 inactivated virus in mice. Overall, the Flu-RBD VLP vaccine is a promising candidate for combating COVID-19, influenza A, and coinfection.
Zhenzhen Wang et al.
A SARS-CoV-2 and influenza double hit vaccine based on RBD-conjugated inactivated influenza A virus
Science, June 2023; doi/10.1126/sciadv.abo4100
Abstract
The circulating flu viruses merging with the ongoing COVID-19 pandemic raises a more severe threat that promotes the infectivity of SARS-CoV-2 associated with higher mortality rates. Here, we conjugated recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein onto inactivated influenza A virus (Flu) to develop a SARS-CoV-2 virus-like particle (VLP) vaccine with two-hit protection. This double-hit vaccine (Flu-RBD) not only induced protective immunities against SARS-CoV-2 but also remained functional as a flu vaccine. The Flu core improved the retention and distribution of Flu-RBD vaccine in the draining lymph nodes, with enhanced immunogenicity. In a hamster model of live SARS-CoV-2 infection, two doses of Flu-RBD efficiently protected animals against viral infection. Furthermore, Flu-RBD VLP elicited a strong neutralization activity against both SARS-CoV-2 Delta pseudovirus and wild-type influenza A H1N1 inactivated virus in mice. Overall, the Flu-RBD VLP vaccine is a promising candidate for combating COVID-19, influenza A, and coinfection.
Rosemary J. Boyton, Daniel M. Altmann
Redirected vaccine imprinting by co-administration of COVID-19 and influenza vaccines
The Lancet, May 2023; doi.org/10.1016/j.lanepe.2023.100644
Abstract
Over the past two years it has become evident that the winter months can bring devastating triple-peaks of COVID-19, influenza and RSV, with potential to add to excess mortality and stretch healthcare provision. A number of studies, straddling different countries, age-groups, and combinations of different influenza vaccines and COVID-19 boosters have now reported on findings with respect to co-administering the two vaccines compared to giving one or the other first.1, 2, 3, 4, 5 The endpoints have comprised adverse event profiles and immunogenicity, although with no data as yet on efficacy. A new addition to this important dataset comes with publication of the TACTIC study – over-60s given Pfizer mRNA booster first and quadrivalent influenza vaccine 3-weeks later, quadrivalent influenza vaccine with Pfizer booster 3-weeks later, both simultaneously or Pfizer mRNA booster alone.6 Collectively, previous studies had reassured that co-administration was generally non-inferior to individual vaccines, but as the new TACTIC study from Dulfer and colleagues shows the devil is in the detail.
TACTIC enrolled 154 individuals over 60 years of age into a single-blind, placebo-controlled randomized clinical trial comparing previously fully COVID-19 vaccinated individuals in COVID-19/influenza booster regimens as follows: quadrivalent influenza (Vaxigrip Tetra) followed by Pfizer (BNT162b2) booster 3-weeks later, Pfizer booster followed 3-weeks later by influenza vaccination, co-administration of the two vaccines or COVID-19 booster only (reference group). The authors report antibody binding data for ancestral spike and neutralizing antibody data against spike D614G, Delta and BA.1 Omicron variants of concern. Importantly, this study found that co-administration compared to booster vaccination alone did not meet the pre-defined criteria for non-inferiority for the primary outcome of IgG binding against spike protein of SARS-CoV-2 and showed less potent neutralization against Delta and Omicron BA.1 variants.6 That is, when using an immunological assay of greater current, functional relevance to protection than simple antibody-binding assays to the original spike protein, the study finds a significantly reduced response.
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While a number of studies show marginally diminished immunity to spike in COVID-19/influenza co-administration protocols, the diminished Delta and Omicron neutralization data shown here is the most noteworthy. Whether the public health advantage of the convenience of co-administration (and thus potentially greater compliance) outweighs any loss in COVID-19 vaccine immunogenicity against current or future variants of concern will need to be further evaluated. The interesting question is how to explain the demonstrable interplay between concurrent vaccines, presumably targeted by non-overlapping repertoires of B cells. The old observation of ‘vaccine interference’ between live attenuated viruses is poorly resolved at a mechanistic level. The observations reported in the TACTIC study following concurrent influenza and COVID-19 booster vaccination seem to be a distinct phenomenon. While this is further investigated, and in order to distinguish from the somewhat confusing term of ‘vaccine interference’ we propose a working term of ‘redirected vaccine imprinting’
Lea Portmann et al.
Hospital Outcomes of Community-Acquired SARS-CoV-2 Omicron Variant Infection Compared With Influenza Infection in Switzerland
Jamanetwork, Februaery 2023; doi:10.1001/jamanetworkopen.2022.55599
Abstract
Importance With the ongoing COVID-19 pandemic, it is crucial to assess the current burden of disease of community-acquired SARS-CoV-2 Omicron variant in hospitalized patients to tailor appropriate public health policies. Comparisons with better-known seasonal influenza infections may facilitate such decisions.
Objective To compare the in-hospital outcomes of patients hospitalized with the SARS-CoV-2 Omicron variant with patients with influenza.
Design, Setting, and Participants This cohort study was based on a national COVID-19 and influenza registry. Hospitalized patients aged 18 years and older with community-acquired SARS-CoV-2 Omicron variant infection who were admitted between January 15 and March 15, 2022 (when B.1.1.529 Omicron predominance was >95%), and hospitalized patients with influenza A or B infection from January 1, 2018, to March 15, 2022, where included. Patients without a study outcome by August 30, 2022, were censored. The study was conducted at 15 hospitals in Switzerland.
Exposures Community-acquired SARS-CoV-2 Omicron variant vs community-acquired seasonal influenza A or B.
Main Outcomes and Measures Primary and secondary outcomes were defined as in-hospital mortality and admission to the intensive care unit (ICU) for patients with the SARS-CoV-2 Omicron variant or influenza. Cox regression (cause-specific and Fine-Graysubdistribution hazard models) was used to account for time-dependency and competing events, with inverse probability weighting to adjust for confounders with right-censoring at day 30.
Conclusions and Relevance The data from this prospective, multicenter cohort study suggest a significantly increased risk of in-hospital mortality for patients with the SARS-CoV-2 Omicron variant vs those with influenza, while ICU admission rates were similar.
Young J. Juhn et al.
Incidence of Respiratory Syncytial Virus Infection in Older Adults Before and During the COVID-19 Pandemic
JAMA, January 2023; doi:10.1001/jamanetworkopen.2022.50634
Abstract
Importance: Little is known about the burden and outcomes of respiratory syncytial virus (RSV)–positive acute respiratory infection (ARI) in community-dwelling older adults.
Objective: To assess the incidence of RSV-positive ARI before and during the COVID-19 pandemic, and to assess outcomes for RSV-positive ARI in older adults.
Design, Setting, and Participants: This was a community-based cohort study of adults residing in southeast Minnesota that followed up with 2325 adults aged 50 years or older for 2 RSV seasons (2019-2021) to assess the incidence of RSV-positive ARI. The study assessed outcomes at 2 to 4 weeks, 6 to 7 months, and 12 to 13 months after RSV-positive ARI.
Exposure RSV-positive and -negative ARI.
Main Outcomes and Measures RSV status was the main study outcome. Incidence and attack rates of RSV-positive ARI were calculated during each RSV season, including before (October 2019 to April 2020) and during (October 2020 to April 2021) COVID-19 pandemic, and further calculated during non-RSV season (May to September 2021) for assessing impact of COVID-19. The self-reported quality of life (QOL) by Short-Form Health Survey-36 (SF-36) and physical functional measures (eg, 6-minute walk and spirometry) at each time point was assessed.
Results In this study of 2325 participants, the median (range) age of study participants was 67 (50-98) years, 1380 (59%) were female, and 2240 (96%) were non-Hispanic White individuals. The prepandemic incidence rate of RSV-positive ARI was 48.6 (95% CI, 36.9-62.9) per 1000 person-years with a 2.50% (95% CI, 1.90%-3.21%) attack rate. No RSV-positive ARI case was identified during the COVID-19 pandemic RSV season. Incidence of 10.2 (95% CI, 4.1-21.1) per 1000 person-years and attack rate of 0.42%; (95% CI, 0.17%-0.86%) were observed during the summer of 2021. Based on prepandemic RSV season results, participants with RSV-positive ARI (vs matched RSV-negative ARI) reported significantly lower QOL adjusted mean difference (limitations due to physical health, −16.7 [95% CI, −31.8 to −1.8]; fatigue, −8.4 [95% CI, −14.3 to −2.4]; and difficulty in social functioning, −11.9 [95% CI, −19.8 to −4.0] within 2 to 4 weeks after RSV-positive ARI [ie, short-term outcome]). Compared with participants with RSV-negative ARI, those with RSV-positive ARI also had lower QOL (fatigue: −4.0 [95% CI, −8.5 to −1.3]; difficulty in social functioning, −5.8 [95% CI, −10.3 to −1.3]; and limitation due to emotional problem, −7.0 [95% CI, −12.7 to −1.3] at 6 to 7 months after RSV-positive ARI [intermediate-term outcome]; fatigue, −4.4 [95% CI, −7.3 to −1.5]; difficulty in social functioning, −5.2 [95% CI, −8.7 to −1.7] and limitation due to emotional problem, −5.7 [95% CI, −10.7 to −0.6] at 12-13 months after RSV-positive ARI [ie, long-term outcomes]) independent of age, sex, race and/or ethnicity, socioeconomic status, and high-risk comorbidities.
Conclusions and Relevance In this cohort study, the burden of RSV-positive ARI in older adults during the pre-COVID-19 period was substantial. After a reduction of RSV-positive ARI incidence from October 2020 to April 2021, RSV-positive ARI re-emerged during the summer of 2021. RSV-positive ARI was associated with significant long-term lower QOL beyond the short-term lower QOL in older adults.
Ratti M. et al.
Vaccination Strategies against Seasonal Influenza in Long Term Care Setting: Lessons from a Mathematical Modelling Study
MDPI, December 2022; doi.org/10.3390/vaccines11010032
Abstract
Background: seasonal influenza in nursing homes is a major public health concern, since in EU 43,000 long term care (LTC) facilities host an estimated 2.9 million elderly residents. Despite specific vaccination campaigns, many outbreaks in such institutions are occasionally reported. We explored the dynamics of seasonal influenza starting from real data collected from a nursing home located in Italy and a mathematical model. Our aim was to identify the best vaccination strategy to minimize cases (and subsequent complications) among the guests. Materials and methods: after producing the contact matrices with surveys of both the health care workers (HCW) and the guests, we developed a mathematical model of the disease. The model consists of a classical SEIR part describing the spreading of the influenza in the general population and a stochastic agent based model that formalizes the dynamics of the disease inside the institution. After a model fit of a baseline scenario, we explored the impact of varying the HCW and guests parameters (vaccine uptake and vaccine efficacy) on the guest attack rates (AR) of the nursing home.
Conclusion: from our findings we can conclude that a nursing home is still an environment at high risk of influenza transmission but the shift change room and the handover situation carry no higher relative risk. Therefore, additional preventive measures in this circumstance may be unnecessary. In a closed environment such as a LTC facility, the vaccination of guests, rather than HCWs, may still represent the cornerstone of an effective preventive strategy. Finally, we think that the extensive inclusion of real life data into mathematical models is promising and may represent a starting point for further applications of this methodology.
Gerco den Hartog et al .
Decline of RSV-specific antibodies during the COVID-19 pandemic
The Lancet, December 2022;doi.org/10.1016/S1473-3099(22)00763-0
Abstract
Hospitalisations due to respiratory syncytial virus (RSV) infections largely decreased after social distancing measures were introduced to control the COVID-19 pandemic. Lifting these measures resulted in out-of-season RSV activity, sometimes exceeding the incidence of hospitalisations observed in regular seasons.1, 2, 3 Declining immunity due to reduced exposure to the virus may contribute to this altered epidemiology.1, 4, 5 Bardsley and colleagues1 showed that the combination of laboratory, clinical, and syndromic data capture the impact of RSV activity, yet did not provide insight into the proposed decline in immunity. To investigate this effect, we analysed sera of 558 randomly selected participants of a prospective nationwide study in the Netherlands for changes in IgG antibody concentrations to the RSV post-fusion F protein.
These data support the assumption that RSV-specific antibody concentrations declined during the COVID-19 pandemic in all age groups and are in line with a previous report showing decay of antibodies to RSV.5 We do not have data on RSV-specific antibody kinetics in our cohort before the pandemic and there are relatively large variations between individuals, so the effect on susceptibility to RSV is not clear yet. Antibodies to the F protein, especially in pre-fusion confirmation, have an important role in the neutralisation of RSV and were previously shown to correlate well with virus neutralisation.7 However, the degree to which virus neutralisation is affected and the exact correlation with immune protection are yet to be determined.8 Following this preliminary analysis, additional timepoints, including follow-up samples, are being investigated to support and extend these findings. In conclusion, monitoring changes in antibody concentrations could identify populations susceptible to RSV infection.
Sparks R et al.
Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19
Nature, January 2023; doi.org/10.1038/s41586-022-05670-5
Abstract
Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood1–4. Here we use systems immunology approaches, including longitudinal multimodal single cell analysis (surface proteins, transcriptome, and V(D)J sequences), to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean: 151 days after diagnosis) and 40 age- and sex-matched controls who never had COVID-19. Our study reveals sex-dimorphic impacts of prior mild COVID-19 and suggests that viral infections in humans can establish new set-points impacting future immune responses in an antigen-agnostic manner.
Intensified circulation of respiratory syncytial virus (RSV) and associated hospital burden in the EU/EEA
Abstract
In recent weeks, respiratory syncytial virus (RSV) circulation in the EU/EEA has intensified, with increasing transmission rates in all population groups and an earlier-than-usual start of the season. Several EU/EEA countries are experiencing high RSV circulation and the number of severe acute respiratory infections (SARI) due to RSV is increasing. At this time of the year RSV infections are not unusual, however this year there is more RSV activity and it began earlier than in pre-COVID-19 seasons.
RSV infection generally causes mild disease, but the severity of clinical manifestations varies considerably. Those most affected by RSV-associated severe disease are children below five years (particularly infants under six months), adults aged 65 years and above and individuals with specific comorbidities. Hospitalisations caused by RSV and other respiratory pathogens, such as influenza virus and SARS-CoV-2, are increasing in a number of Member States, and are already placing pressure on healthcare systems.
Although several vaccine candidates are in clinical development for infants, pregnant women and older adults, there are currently no licensed vaccines available to prevent RSV infection. Effective passive immune prophylaxis is available and this is recommended for high-risk infants. At present, there are no specific therapeutic options for RSV infection, and treatment of hospitalised patients is mainly supportive.
Combining the probability of infection and the impact of the associated disease, the risk from RSV infection is assessed as low for the general population, and high for infants under six months, adults 65 years and above and individuals with specific comorbidities.
The risk that co-circulating RSV, influenza virus and SARS-CoV-2 will place pressure on EU/EEA healthcare systems in the coming weeks is assessed as high.
Where possible, implement and improve surveillance of RSV and testing for respiratory pathogens. ECDC encourages Member States to continue reporting influenza, SARS-CoV-2, and RSV infection and hospitalisation data from sentinel and non-sentinel sources.
Arevalo C.P et al.
A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes
Science, November 2022; doi/10.1126/science.abm0271
Abstract
Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective prepandemic vaccines because it is uncertain which influenza virus subtype will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA)–lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known influenza A virussubtypes and influenza B virus lineages. This multivalent vaccine elicited high levels of cross-reactiveand subtype-specific antibodies in mice and ferrets that reacted to all 20 encoded antigens.Vaccination protected mice and ferrets challenged with matched and mismatched viral strains, and this protection was at least partially dependent on antibodies. Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses by simultaneously inducing antibodies against multiple antigens.
Sheikh Taslim Ali et al.
Prediction of upcoming global infection burden of influenza seasons after relaxation of public health and social measures during the COVID-19 pandemic: a modelling study
Lancet, November 2022; doi.org/10.1016/S2214-109X(22)00358-8
Abstract
The authors aimed to assess the effect of COVID-19 PHSMs on the transmissibility of influenza viruses and to predict upcoming influenza epidemics.
S. M. Hosseini-Moghaddam et al.
Association of influenza vaccination with SARS-CoV-2 infection and associated hospitalization and mortality among patients aged 66 years or older.
JAMA Network Open, September 2022; doi:10.1001/jamanetworkopen.2022.33730
Abstract
Vaccine effectiveness studies have rarely implemented strategies to reduce the healthy vaccine e bias arising from differences in health care–seeking behavior between vaccinated and unvaccinated individuals. Although previous observational studies suggest that influenza vaccination is associated with a reduced risk of SARS-CoV-2–associatedoutcomes, the healthy vaccine e bias may have led to overestimating the vaccination effect.
R. Rubin
The Dreaded “Twindemic” of Influenza and COVID-19 Has Not Yet Materialized—Might This Be the Year?
JAMA, September 2022; doi:10.1001/jama.2022.15062
Abstract
The epidemiologist Michael Osterholm, likens predicting a flu season’s severity to forecasting a hurricane’s strength and its exact path 5 days before it makes landfall.
J. Yang et al.
Co-existence and co-infection of influenza A viruses and coronaviruses: public health challenges
Innovation (Camb), August 2022; doi: 10.1016/j.xinn.2022.100306
Abstract
Since the 20th century, humans have lived through five pandemics caused by influenza A viruses (IAVs) (H1N1/1918, H2N2/1957, H3N2/1968, and H1N1/2009), and the coronavirus (CoV) SARS-CoV-2. IAVs and CoVs both have broad host ranges and share multiple hosts. Virus co-circulation and even co-infections facilitate genetic reassortment among IAVs and recombination among CoVs, further altering virus evolution dynamics and generating novel variants with increased cross-species transmission risk. Moreover, SARS-CoV-2 may maintain long-term circulation in humans as seasonal IAVs. Co-existence and co-infection of both viruses in humans could alter disease transmission patterns and aggravate disease burden. Herein, we demonstrate how virus-host ecology correlates with the co-existence and co-infection of IAVs and/or CoVs, further affecting virus evolution and disease dynamics and burden, calling for active virus surveillance and countermeasures for future public health challenges.
R.K. Leuchter et al.
Association between Covid-19 Vaccination and Influenza Vaccination Rates
The New England J of Medicine, June 2022;doi: 10.1056/NEJMc2204560
Abstract
The polarizing nature of vaccination against coronavirus disease 2019 (Covid-19) within the United States threatens public health and has contributed to variable statewide vaccine uptake that ranged from 50 to 80% as of January 2022.Given the divided national landscape and anecdotal evidence from our own patients, we hypothesized that low Covid-19 vaccination rates would be associated with decreases in influenza vaccination rates.
