Cross-reactive HA and NA-specific ADCC responses are induced by TVV+MM.

<p>Mice (n = 8/group) were immunized once or twice with TVV or TVV+MM. Three weeks later, serum samples were obtained and tested for H5N1 A/Hong Kong/156/97 cross-reactive HAI responses (A), neutralizing antibody responses (B), HA-specific antibodies (C) and NA-specific antibodies (D) or ADCC responses against H5 expressing cells (E) or N1 expressing cells (F). Black bars indicate medians of log-2 transformed HAI and neutralizing titers (NT) or log-10 transformed ELISA titers (EU). Error bars in ADCC assays indicate the standard error of the duplicate means. Control in HAI assay = H5/HK specific sheep serum.</p

CD4⁺ and CD8⁺ T cells both contribute to H5N1 protection.

<p>Mice (n = 8-10/group) were immunized once with TVV+MM or PBS as negative control 4 weeks before challenge and (A) CD8⁺ or the combination of CD4⁺ and CD8⁺ T cells were depleted or (B) CD4⁺ T cells only were depleted with antibodies injected 4 days and 1 day before challenge. Mice were challenged with 12.5xLD₅₀ of wild type H5N1 A/Hong Kong/156/97 and monitored for 21 days for (A and B) survival and (C and D) bodyweight-loss. Graphs A and B represent the Kaplan-Meier survival curves and graphs C and D represent mean bodyweight change with 95% confidence interval.</p

Exploring the role of antiviral nasal sprays in the control of emerging respiratory infections in the community

Introduction: The COVID-19 pandemic has demonstrated that there is an unmet need for the development of novel prophylactic antiviral treatments to control the outbreak of emerging respiratory virus infections. Passive antibody-based immunisation approaches such as intranasal antibody prophylaxis have the potential to provide immediately accessible universal protection as they act directly at the most common route of viral entry, the upper respiratory tract. The need for such products is very apparent for SARS-CoV-2 at present, given the relatively low effectiveness of vaccines to prevent infection and block virus onward transmission. We explore the benefits and challenges of the use of antibody-based nasal sprays prior and post exposure to the virus. Methods: The classic susceptible-exposed-infectious-removed (SEIR) mathematical model was extended to describe the potential population-level impact of intranasal antibody prophylaxis on controlling the spread of an emerging respiratory infection in the community. Results: Intranasal administration of monoclonal antibodies provides only a short-term protection to the mucosal surface. Consequently, sustained intranasal antibody prophylaxis of a substantial proportion of the population would be needed to contain infections. Post-exposure prophylaxis against the development of severe disease would be essential for the overall reduction in hospital admissions. Conclusion: Antibody-based nasal sprays could provide protection against infection to individuals that are likely to be exposed to the virus. Large-scale administration for a long period of time would be challenging. Intranasal antibody prophylaxis alone cannot prevent community-wide transmission of the virus. It could be used along with other protective measures, such as non-pharmaceutical interventions, to bridge the time required to develop and produce effective vaccines, and complement active immunisation strategies.</p

SARS-CoV-2 elicits non-sterilizing immunity and evades vaccine-induced immunity: implications for future vaccination strategies

Neither vaccination nor natural infection result in long-lasting protection against SARS-COV-2 infection and transmission, but both reduce the risk of severe COVID-19. To generate insights into optimal vaccination strategies for prevention of severe COVID-19 in the population, we extended a Susceptible-Exposed-Infectious-Removed (SEIR) mathematical model to compare the impact of vaccines that are highly protective against severe COVID-19 but not against infection and transmission, with those that block SARS-CoV-2 infection. Our analysis shows that vaccination strategies focusing on the prevention of severe COVID-19 are more effective than those focusing on creating of herd immunity. Key uncertainties that would affect the choice of vaccination strategies are: (1) the duration of protection against severe disease, (2) the protection against severe disease from variants that escape vaccine-induced immunity, (3) the incidence of long-COVID and level of protection provided by the vaccine, and (4) the rate of serious adverse events following vaccination, stratified by demographic variables

Serum antibodies confer partial protection against H5N1.

<p>(A) Mice (n = 8/group) were immunized once with TVV+MM or PBS as negative control 4 weeks before challenge. (B) Recipient mice (n = 11-12/group) received 400μl immune sera of 1-time or 2-times TVV+MM immunized donors or naïve serum intraperitoneally one day before challenge. Mice were challenged with 12.5xLD₅₀ of wild type H5N1 A/Hong Kong/156/97 and monitored for 21 days for survival and weight-loss. Graphs A and B represent the Kaplan-Meier survival curves and graphs C and D represent mean bodyweight change with 95% confidence interval. ST = serum transfer.</p

H5 and N1 cross-reactive T cells are induced by TVV+MM.

<p>Mice (n = 8/group) were immunized once or twice with TVV or TVV+MM. Three weeks later, spleens were harvested. The number of IFN-γ producing T cells was determined by ex vivo stimulation of splenocytes with peptide pools consisting of 15-mer peptides that cover the total (A) HA or (B) NA sequence of H5/HK with an 11-mer overlap. Black bars indicate medians of IFN-γ⁺ T cells per 10⁶ splenocytes. SFU = Spot forming units.</p

Matrix-M Adjuvated Seasonal Virosomal Influenza Vaccine Induces Partial Protection in Mice and Ferrets against Avian H5 and H7 Challenge

<div><p>There is a constant threat of zoonotic influenza viruses causing a pandemic outbreak in humans. It is virtually impossible to predict which virus strain will cause the next pandemic and it takes a considerable amount of time before a safe and effective vaccine will be available once a pandemic occurs. In addition, development of pandemic vaccines is hampered by the generally poor immunogenicity of avian influenza viruses in humans. An effective pre-pandemic vaccine is therefore required as a first line of defense. Broadening of the protective efficacy of current seasonal vaccines by adding an adjuvant may be a way to provide such first line of defense. Here we evaluate whether a seasonal trivalent virosomal vaccine (TVV) adjuvated with the saponin-based adjuvant Matrix-M (MM) can confer protection against avian influenza H5 and H7 virus strains in mice and ferrets. We demonstrate that mice were protected from death against challenges with H5N1 and H7N7, but that the protection was not complete as evidenced by severe clinical signs. In ferrets, protection against H7N9 was not observed. In contrast, reduced upper and lower respiratory tract viral loads and reduced lung pathology, was achieved in H5N1 challenged ferrets. Together these results suggest that, at least to some extent, Matrix-M adjuvated seasonal virosomal influenza vaccine can serve as an interim measure to decrease morbidity and mortality associated with a pandemic outbreak.</p></div

Ferrets are not protected against highly pathogenic H7N9 after TVV+MM vaccination.

<p>Groups of 7–8 ferrets received two intramuscular injections with TVV, TVV+MM, PBS, PBS+MM or inactivated H7N9 virus as positive control (Control). 4 weeks later the animals were challenged with a sub-lethal dose of 10^5.5 TCID₅₀ of influenza A H7N9 A/Anhui/1/2013. Ferrets were monitored for 4 consecutive days and sacrificed at day 4 post challenge. (A) Infectious viral load in lung tissue (B) infectious throat viral load (day 1 to 4), (C) percentage of body weight change during the observation period (D) lung weight as determined after sacrifice. Dots indicate individual animals and horizontal lines represent group means (A and D). Lines represent group mean with 95% confidence interval (B) or the interquartile range (C). Asterisks indicate statistically significant differences compared to PBS injected animals (*<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001, according to the materials and methods section).</p

TVV+MM induces cross-reactive H5 and H7 antibody responses.

<p>Mice (n = 9-10/group) were immunized 1x or 2x with TVV with or without MM. 27 days later (1 day before challenge) individual serum samples were obtained and tested for (A) vaccine homologous recH1 of A/California/07/07, (B) vaccine homologous recH3 of the A/Victoria/210/09-like A/Perth/16/09 (98.8% homologous), (C) recH5 of A/Hong Kong/156/97, and (D) recH7 of A/Netherlands/219/03 (99.6% homologous to the challenge strain A/chicken/Netherlands/621557/03) antibody responses. Serum pools of mice (n = 50/group) that received 1x or 2x TVV+MM or no immunization (-) were tested for (E) vaccine homologous recN1 A/California/04/09 and (F) recN1 of A/Hong Kong/156/97 reactive antibody responses. Black bars indicate medians of log-10 transformed ELISA titers (EU). Asterisks indicate statistically significant differences compared to the vehicle control group (*p<0.05, **p<0.01, ***p<0.001, according to the materials and methods section).</p

Ferrets are partially protected against highly pathogenic H5N1 after TVV+MM vaccination.

<p>Groups of 7–8 ferrets received two intramuscular injections with TVV, TVV+MM, PBS, PBS+MM or inactivated H5H1 virus as positive control (Control). 4 weeks later the animals were challenged with a sub-lethal dose of 10⁴ TCID₅₀ of influenza A H5N1 A/Indonesia/05/2005. Ferrets were monitored for 4 consecutive days and sacrificed at day 4 post challenge. (A) Infectious viral load in lung tissue (B) infectious throat viral load (day 1 to 4), (C) percentage of body weight change during the observation period and (D) lung weight as determined after sacrifice. Dots indicate individual animals and horizontal lines represent group means (A and D). Lines represent group mean with 95% confidence interval (B) or the interquartile range (C). Asterisks indicate statistically significant differences compared to PBS injected animals (*<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001, according to the materials and methods section).</p