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1.
J Virol ; 96(18): e0133722, 2022 09 28.
Article in English | MEDLINE | ID: covidwho-2019728

ABSTRACT

COVID-19 and influenza are both highly contagious respiratory diseases that have been serious threats to global public health. It is necessary to develop a bivalent vaccine to control these two infectious diseases simultaneously. In this study, we generated three attenuated replicating recombinant vesicular stomatitis virus (rVSV)-based vaccine candidates against both SARS-CoV-2 and influenza viruses. These rVSV-based vaccines coexpress SARS-CoV-2 Delta spike protein (SP) bearing the C-terminal 17 amino acid (aa) deletion (SPΔC) and I742A point mutation, or the SPΔC with a deletion of S2 domain, or the RBD domain, and a tandem repeat harboring four copies of the highly conserved influenza M2 ectodomain (M2e) that fused with the Ebola glycoprotein DC-targeting/activation domain. Animal immunization studies have shown that these rVSV bivalent vaccines induced efficient humoral and cellular immune responses against both SARS-CoV-2 SP and influenza M2 protein, including high levels of neutralizing antibodies against SARS-CoV-2 Delta and other variant SP-pseudovirus infections. Importantly, immunization of the rVSV bivalent vaccines effectively protected hamsters or mice against the challenges of SARS-CoV-2 Delta variant and lethal H1N1 and H3N2 influenza viruses and significantly reduced respiratory viral loads. Overall, this study provides convincing evidence for the high efficacy of this bivalent vaccine platform to be used and/or easily adapted to produce new vaccines against new or reemerging SARS-CoV-2 variants and influenza A virus infections. IMPORTANCE Given that both COVID-19 and influenza are preferably transmitted through respiratory droplets during the same seasons, it is highly advantageous to develop a bivalent vaccine that could simultaneously protect against both COVID-19 and influenza. In this study, we generated the attenuated replicating recombinant vesicular stomatitis virus (rVSV)-based vaccine candidates that target both spike protein of SARS-Cov-2 Delta variant and the conserved influenza M2 domain. Importantly, these vaccine candidates effectively protected hamsters or mice against the challenges of SARS-CoV-2 Delta variant and lethal H1N1 and H3N2 influenza viruses and significantly reduced respiratory viral loads.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Vaccines, Combined , Vesicular Stomatitis , Amino Acids/genetics , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Cricetinae , Glycoproteins/genetics , Glycoproteins/immunology , Humans , Influenza A Virus, H3N2 Subtype , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Mice , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Combined/immunology , Vaccines, Synthetic/genetics , Vesiculovirus/immunology
2.
J Virol ; 96(15): e0068922, 2022 08 10.
Article in English | MEDLINE | ID: covidwho-1949995

ABSTRACT

Vaccines targeting SARS-CoV-2 have been shown to be highly effective; however, the breadth against emerging variants and the longevity of protection remains unclear. Postimmunization boosting has been shown to be beneficial for disease protection, and as new variants continue to emerge, periodic (and perhaps annual) vaccination will likely be recommended. New seasonal influenza virus vaccines currently need to be developed every year due to continual antigenic drift, an undertaking made possible by a robust global vaccine production and distribution infrastructure. To create a seasonal combination vaccine targeting both influenza viruses and SARS-CoV-2 that is also amenable to frequent reformulation, we have developed an influenza A virus (IAV) genetic platform that allows the incorporation of an immunogenic domain of the SARS-CoV-2 spike (S) protein onto IAV particles. Vaccination with this combination vaccine elicited neutralizing antibodies and provided protection from lethal challenge with both pathogens in mice. This approach may allow the leveraging of established influenza vaccine infrastructure to generate a cost-effective and scalable seasonal vaccine solution for both influenza and coronaviruses. IMPORTANCE The rapid emergence of SARS-CoV-2 variants since the onset of the pandemic has highlighted the need for both periodic vaccination "boosts" and a platform that can be rapidly reformulated to manufacture new vaccines. In this work, we report an approach that can utilize current influenza vaccine manufacturing infrastructure to generate combination vaccines capable of protecting from both influenza virus- and SARS-CoV-2-induced disease. The production of a combined influenza/SARS-CoV-2 vaccine may represent a practical solution to boost immunity to these important respiratory viruses without the increased cost and administration burden of multiple independent vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , Influenza A virus , Influenza Vaccines , Orthomyxoviridae Infections , SARS-CoV-2 , Vaccines, Combined , Virion , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Humans , Influenza A virus/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Influenza, Human/immunology , Influenza, Human/prevention & control , Mice , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , SARS-CoV-2/classification , SARS-CoV-2/immunology , Vaccines, Combined/administration & dosage , Vaccines, Combined/immunology
3.
PLoS One ; 17(2): e0255495, 2022.
Article in English | MEDLINE | ID: covidwho-1910477

ABSTRACT

BACKGROUND: Vaccine hesitancy is increasing. We assessed attitudes toward influenza and COVID-19 vaccines and the relation between hesitancy to influenza vaccine and hesitancy towards COVID-19 vaccines. METHODS: A structured questionnaire administered during September 2020 to a representative sample of the Jewish Israeli population assessed attitudes and acceptance of influenza and COVID-19 vaccines. Factors for vaccine hesitancy were determined using logistic regression. Questionnaires were administered prior to the release of clinical data regarding efficacy and safety of COVID-19 vaccines and prior to vaccine rollout. RESULTS: We approached 10,625 people, of these 2,080 responded (19%), and 2,024 completed the questionnaire (97.3%), 64.9% aged 15-64 years and 35.1% aged ≥65 years. 37% had co-morbidities. 43.5% experienced financial deterioration due to the pandemic. 65.9% received influenza vaccine ≥1 time in the past. Influenza vaccination rates were higher in the elderly (81.8%). Reasons for influenza vaccine hesitancy were opinions that the vaccine is ineffective (27.1%), and fear of side effects (29.3%). 8.2% of people aged 16-64 and 13.8% of people aged≥65 refused to be vaccinated at least once over the course of one's lifetime. Percent of responders willing to receive a COVID-19 vaccine were higher than percent of responders willing to receive the influenza vaccine both in people aged 16-64 years (942 (72.3%) vs. 38.4%, respectively) and in people 65 years and older (84.0% vs. 76.8%, respectively). Hesitancy towards COVID-19 vaccine was associated with hesitancy towards other vaccines. Only 26.8% would participate in a COVID-19 vaccine trial. CONCLUSIONS: Willingness to receive COVID-19 vaccine was higher than willingness to receive influenza vaccine. The results point to areas of fear from influenza vaccines side effects and lack of knowledge regarding influenza vaccines effectiveness that can be addressed to increase acceptance. Hesitancy towards other vaccines was associated with hesitancy towards COVID-19 vaccination.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/epidemiology , COVID-19/immunology , Health Knowledge, Attitudes, Practice , Influenza Vaccines/immunology , Jews , Pandemics , Adolescent , Adult , Age Factors , Aged , Female , Humans , Israel/epidemiology , Male , Middle Aged , Seasons , Surveys and Questionnaires , Young Adult
4.
Front Immunol ; 13: 782198, 2022.
Article in English | MEDLINE | ID: covidwho-1902963

ABSTRACT

Misunderstanding temporal coincidence of adverse events during mass vaccination and invalid assessment of possible safety concerns have negative effects on immunization programs, leading to low immunization coverage. We conducted this systematic review and meta-analysis to identify the incidence rates of GBS that are temporally associated with viral vaccine administration but might not be attributable to the vaccines. By literature search in Embase and PubMed, we included 48 publications and 2,110,441,600 participants. The pooled incidence rate of GBS was 3.09 per million persons (95% confidence interval [CI]: 2.67 to 3.51) within six weeks of vaccination, equally 2.47 per 100,000 person-year (95%CI: 2.14 to 2.81). Subgroup analyses illustrated that the pooled rates were 2.77 per million persons (95%CI: 2.47 to 3.07) for individuals who received the influenza vaccine and 2.44 per million persons (95%CI: 0.97 to 3.91) for human papillomavirus (HPV) vaccines, respectively. Our findings evidence the GBS-associated safety of virus vaccines. We present a reference for the evaluation of post-vaccination GBS rates in mass immunization campaigns, including the SARS-CoV-2 vaccine.


Subject(s)
COVID-19 Vaccines/adverse effects , Guillain-Barre Syndrome/epidemiology , Influenza Vaccines/adverse effects , Mass Vaccination/adverse effects , Papillomavirus Vaccines/adverse effects , Alphapapillomavirus/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/immunology , Population Surveillance , SARS-CoV-2/immunology
5.
Vet Microbiol ; 271: 109491, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1882620

ABSTRACT

Viral infectious pathogens, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, can cause extremely high infection rates and mortality in humans. Therefore, it is urgent to develop an effective vaccine against coronavirus and influenza virus infection. Herein, we used the influenza virus as a vector to express the SARS-CoV-2 spike receptor-binding domain (RBD) and hemagglutinin-esterase-fusion (HEF) protein of the influenza C virus. We then evaluated the feasibility and effectiveness of this design strategy through experiments in vitro and in vivo. The results showed that the chimeric viruses could stably express the HEF protein and the SARS-CoV-2 spike RBD at a high level. BALB/c mice, infected with the chimeric virus, exhibited mild clinical symptoms, yet produced high specific antibody levels against RBD and HEF, including neutralizing antibodies. Importantly, high neutralizing antibodies could be retained in the sera of mice for at least 20 weeks. Altogether, our data provided a new strategy for developing safe and effective COVID-19 and influenza virus vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , Influenza Vaccines , Orthomyxoviridae , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Influenza Vaccines/immunology , Mice , Mice, Inbred BALB C , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus
6.
J Virol ; 96(5): e0179121, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1799229

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal influenza viruses are cocirculating in the human population. However, only a few cases of viral coinfection with these two viruses have been documented in humans with some people having severe disease and others mild disease. To examine this phenomenon, ferrets were coinfected with SARS-CoV-2 and human seasonal influenza A viruses (IAVs; H1N1 or H3N2) and were compared to animals that received each virus alone. Ferrets were either immunologically naive to both viruses or vaccinated with the 2019 to 2020 split-inactivated influenza virus vaccine. Coinfected naive ferrets lost significantly more body weight than ferrets infected with each virus alone and had more severe inflammation in both the nose and lungs compared to that of ferrets that were single infected with each virus. Coinfected, naive animals had predominantly higher IAV titers than SARS-CoV-2 titers, and IAVs were efficiently transmitted by direct contact to the cohoused ferrets. Comparatively, SARS-CoV-2 failed to transmit to the ferrets that cohoused with coinfected ferrets by direct contact. Moreover, vaccination significantly reduced IAV titers and shortened the viral shedding but did not completely block direct contact transmission of the influenza virus. Notably, vaccination significantly ameliorated influenza-associated disease by protecting vaccinated animals from severe morbidity after IAV single infection or IAV and SARS-CoV-2 coinfection, suggesting that seasonal influenza virus vaccination is pivotal to prevent severe disease induced by IAV and SARS-CoV-2 coinfection during the COVID-19 pandemic. IMPORTANCE Influenza A viruses cause severe morbidity and mortality during each influenza virus season. The emergence of SARS-CoV-2 infection in the human population offers the opportunity to potential coinfections of both viruses. The development of useful animal models to assess the pathogenesis, transmission, and viral evolution of these viruses as they coinfect a host is of critical importance for the development of vaccines and therapeutics. The ability to prevent the most severe effects of viral coinfections can be studied using effect coinfection ferret models described in this report.


Subject(s)
Antibodies, Viral/blood , COVID-19/prevention & control , Coinfection/prevention & control , Influenza Vaccines/immunology , Orthomyxoviridae Infections/prevention & control , Animals , COVID-19/immunology , Female , Ferrets/immunology , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/immunology , Orthomyxoviridae Infections/immunology , Vaccination , Virus Shedding
7.
J Virol ; 96(4): e0157821, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1759290

ABSTRACT

The ongoing SARS-CoV-2 pandemic poses a severe global threat to public health, as do influenza viruses and other coronaviruses. Here, we present chimpanzee adenovirus 68 (AdC68)-based vaccines designed to universally target coronaviruses and influenza. Our design is centered on an immunogen generated by fusing the SARS-CoV-2 receptor-binding domain (RBD) to the conserved stalk of H7N9 hemagglutinin (HA). Remarkably, the constructed vaccine effectively induced both SARS-CoV-2-targeting antibodies and anti-influenza antibodies in mice, consequently affording protection from lethal SARS-CoV-2 and H7N9 challenges as well as effective H3N2 control. We propose our AdC68-vectored coronavirus-influenza vaccine as a universal approach toward curbing respiratory virus-causing pandemics. IMPORTANCE The COVID-19 pandemic exemplifies the severe public health threats of respiratory virus infection and influenza A viruses. The currently envisioned strategy for the prevention of respiratory virus-causing diseases requires the comprehensive administration of vaccines tailored for individual viruses. Here, we present an alternative strategy by designing chimpanzee adenovirus 68-based vaccines which target both the SARS-CoV-2 receptor-binding-domain and the conserved stalk of influenza hemagglutinin. When tested in mice, this strategy attained potent neutralizing antibodies against wild-type SARS-CoV-2 and its emerging variants, enabling an effective protection against lethal SARS-CoV-2 challenge. Notably, it also provided complete protection from lethal H7N9 challenge and efficient control of H3N2-induced morbidity. Our study opens a new avenue to universally curb respiratory virus infection by vaccination.


Subject(s)
COVID-19/prevention & control , Influenza A Virus, H7N9 Subtype/immunology , Influenza Vaccines , Orthomyxoviridae Infections/prevention & control , SARS-CoV-2/immunology , Animals , COVID-19/epidemiology , COVID-19/genetics , COVID-19/immunology , /immunology , Female , HEK293 Cells , Humans , Influenza A Virus, H7N9 Subtype/genetics , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Influenza Vaccines/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Transgenic , Orthomyxoviridae Infections/epidemiology , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/immunology , Pandemics , SARS-CoV-2/genetics
8.
Proc Natl Acad Sci U S A ; 119(13): e2025607119, 2022 03 29.
Article in English | MEDLINE | ID: covidwho-1758459

ABSTRACT

SignificanceAlthough the need for a universal influenza vaccine has long been recognized, only a handful of candidates have been identified so far, with even fewer advancing in the clinical pipeline. The 24-amino acid ectodomain of M2 protein (M2e) has been developed over the past two decades. However, M2e-based vaccine candidates have shortcomings, including the need for several administrations and the lack of sustained antibody titers over time. We report here a vaccine targeting strategy that has the potential to confer sustained and strong protection upon a single shot of a small amount of M2e antigen. The current COVID-19 pandemic has highlighted the importance of developing versatile, powerful platforms for the rapid deployment of vaccines against any incoming threat.


Subject(s)
COVID-19 , Influenza A virus , Influenza Vaccines , Influenza, Human , Viral Matrix Proteins , Viroporin Proteins , Animals , Antibodies, Monoclonal/genetics , Antibodies, Viral/genetics , Antibodies, Viral/immunology , COVID-19/prevention & control , Dendritic Cells/immunology , Humans , Influenza A virus/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/prevention & control , Pandemics/prevention & control , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/immunology , Viroporin Proteins/immunology
10.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Article in English | MEDLINE | ID: covidwho-1671755
11.
Circulation ; 144(18): 1476-1484, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1666519

ABSTRACT

BACKGROUND: Observational and small, randomized studies suggest that influenza vaccine may reduce future cardiovascular events in patients with cardiovascular disease. METHODS: We conducted an investigator-initiated, randomized, double-blind trial to compare inactivated influenza vaccine with saline placebo administered shortly after myocardial infarction (MI; 99.7% of patients) or high-risk stable coronary heart disease (0.3%). The primary end point was the composite of all-cause death, MI, or stent thrombosis at 12 months. A hierarchical testing strategy was used for the key secondary end points: all-cause death, cardiovascular death, MI, and stent thrombosis. RESULTS: Because of the COVID-19 pandemic, the data safety and monitoring board recommended to halt the trial before attaining the prespecified sample size. Between October 1, 2016, and March 1, 2020, 2571 participants were randomized at 30 centers across 8 countries. Participants assigned to influenza vaccine totaled 1290 and individuals assigned to placebo equaled 1281; of these, 2532 received the study treatment (1272 influenza vaccine and 1260 placebo) and were included in the modified intention to treat analysis. Over the 12-month follow-up, the primary outcome occurred in 67 participants (5.3%) assigned influenza vaccine and 91 participants (7.2%) assigned placebo (hazard ratio, 0.72 [95% CI, 0.52-0.99]; P=0.040). Rates of all-cause death were 2.9% and 4.9% (hazard ratio, 0.59 [95% CI, 0.39-0.89]; P=0.010), rates of cardiovascular death were 2.7% and 4.5%, (hazard ratio, 0.59 [95% CI, 0.39-0.90]; P=0.014), and rates of MI were 2.0% and 2.4% (hazard ratio, 0.86 [95% CI, 0.50-1.46]; P=0.57) in the influenza vaccine and placebo groups, respectively. CONCLUSIONS: Influenza vaccination early after an MI or in high-risk coronary heart disease resulted in a lower risk of a composite of all-cause death, MI, or stent thrombosis, and a lower risk of all-cause death and cardiovascular death, as well, at 12 months compared with placebo. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02831608.


Subject(s)
Influenza Vaccines/administration & dosage , Myocardial Infarction/immunology , Double-Blind Method , Female , Humans , Influenza Vaccines/immunology , Male , Middle Aged , Treatment Outcome
12.
Elife ; 102021 11 17.
Article in English | MEDLINE | ID: covidwho-1662831

ABSTRACT

The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. We previously showed that a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages against vaccine antigens can occur. However, it remains to be determined whether seasonal influenza vaccination stimulates additional evolution of vaccine-specific lineages, and previous work has found no significant increase in somatic hypermutation among influenza-binding lineages sampled from the blood following seasonal vaccination in humans. Here, we investigate this issue using a phylogenetic test of measurable immunoglobulin sequence evolution. We first validate this test through simulations and survey measurable evolution across multiple conditions. We find significant heterogeneity in measurable B cell evolution across conditions, with enrichment in primary response conditions such as HIV infection and early childhood development. We then show that measurable evolution following influenza vaccination is highly compartmentalized: while lineages in the blood are rarely measurably evolving following influenza vaccination, lineages containing GC B cells are frequently measurably evolving. Many of these lineages appear to derive from memory B cells. We conclude from these findings that seasonal influenza virus vaccination can stimulate additional evolution of responding B cell lineages, and imply that the poor efficacy of seasonal influenza vaccination is not due to a complete inhibition of vaccine-specific B cell evolution.


When the immune system encounters a disease-causing pathogen, it releases antibodies that can bind to specific regions of the bacterium or virus and help to clear the infection. These proteins are generated by B cells which, upon detecting the pathogen, can begin to mutate and alter the structure of the antibody they produce: the better the antibody is at binding to the pathogen, the more likely the B cell is to survive. This process of evolution produces B cells that make more effective antibodies. After the infection, some of these cells become 'memory B cells' which can be stimulated in to action when the pathogen invades again. Many vaccines also depend on this process to trigger the production of memory B cells that can fight off a specific disease-causing agent. However, it is unclear to what extent memory B cells that already exist are able to continue to evolve and modify their antibodies. This is particularly important for the flu vaccine, as the virus that causes influenza rapidly mutates. To provide high levels of protection, the memory B cells formed following the vaccine may therefore need to evolve to make different antibodies that recognize mutated forms of the virus. It is thought that the low effectiveness of the flu vaccine is partially because the response it triggers does not stimulate additional evolution of memory B cells. To test this theory, Hoehn et al. developed a computational method that can detect the evolution of B cells over time. The tool was applied to samples collected from the blood and lymph nodes (organ where immune cells reside) of people who recently received the flu vaccine. The results were then compared to B cells taken from people after different infections, vaccinations, and other conditions. Hoehn et al. found the degree to which B cells evolve varies significantly between conditions. For example, B cells produced during chronic HIV infections frequently evolved over time, while such evolution was rarely observed during the autoimmune disease myasthenia gravis. The analysis also showed that memory B cells produced by the flu vaccine were able to evolve if recruited to the lymph nodes, but this was rarely detected in B cells in the blood. These findings suggest the low efficacy of the flu vaccine is not due to a complete lack of B cell evolution, but likely due to other factors. For instance, it is possible the evolutionary process it stimulates is not as robust as in other conditions, or is less likely to produce long-lived B cells that release antibodies. More research is needed to explore these ideas and could lead to the development of more effective flu vaccines.


Subject(s)
B-Lymphocytes/immunology , Evolution, Molecular , Germinal Center/immunology , Influenza Vaccines/immunology , Humans , Influenza, Human/virology , Phylogeny , Vaccination
13.
PLoS Pathog ; 18(1): e1010255, 2022 01.
Article in English | MEDLINE | ID: covidwho-1649753

ABSTRACT

Nucleoside modified mRNA combined with Acuitas Therapeutics' lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs' ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cells and humoral immune responses, nor susceptibility towards the lethal challenge of influenza and SARS-CoV-2. However, the combined deletion of these two DC subsets led to a significant decrease in the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cell and humoral immune responses. Despite these observed defects, these mice remained protected from lethal influenza and SARS-CoV-2 challenges. We further found that IL-6, unlike neutrophils, was required to generate normal Tfh cells and antibody responses, but not for protection from influenza challenge. In summary, here we bring evidence that the mRNA-LNP platform can support the induction of protective immune responses in the absence of certain innate immune cells and cytokines.


Subject(s)
COVID-19 Vaccines/immunology , Dendritic Cells/immunology , Influenza Vaccines/immunology , Langerhans Cells/immunology , Liposomes/immunology , Vaccines, Synthetic/immunology , mRNA Vaccines/immunology , Animals , COVID-19/immunology , Mice , Nanoparticles , Orthomyxoviridae Infections/immunology , SARS-CoV-2/immunology
14.
CPT Pharmacometrics Syst Pharmacol ; 11(1): 44-54, 2022 01.
Article in English | MEDLINE | ID: covidwho-1616093

ABSTRACT

The identification of influenza epidemics and assessment of the efficacy of vaccination against this infection are major challenges for the implementation of effective public health strategies, such as vaccination programs. In this study, we developed a new pharmacometric model to evaluate the efficacy of vaccination based on infection surveillance data from the 2010/2011 to 2018/2019 influenza seasons in Japan. A novel susceptible-infected-removed plus vaccination model, based on an indirect response structure with the effect of vaccination, was applied to describe seasonal influenza epidemics using a preseasonal collection of data regarding serological H1 antibody titer positivity and the fraction of virus strains. Using this model, we evaluated Kin (a parameter describing the transmission rate of symptomatic influenza infection) for different age groups. Furthermore, we defined a new parameter (prevention factor) showing the efficacy of vaccination against each viral strain and in different age groups. We found that the prevention factor of vaccination against influenza varied among age groups. Notably, children aged 5-14 years showed the highest Kin value during the 10 influenza seasons and the greatest preventive effect of vaccination (prevention factor = 70.8%). The propagation of influenza epidemics varies in different age groups. Children aged 5-14 years most likely play a leading role in the transmission of influenza. Prioritized vaccination in this age group may be the most effective strategy for reducing the prevalence of influenza in the community.


Subject(s)
Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Influenza, Human/epidemiology , Influenza, Human/immunology , Adolescent , Adult , Age Factors , Aged , Basic Reproduction Number , Child , Child, Preschool , Female , Humans , Infant , Influenza, Human/prevention & control , Influenza, Human/transmission , Japan/epidemiology , Male , Middle Aged , Models, Biological , Seasons , Sentinel Surveillance , Young Adult
15.
Cell Mol Immunol ; 19(2): 234-244, 2022 02.
Article in English | MEDLINE | ID: covidwho-1612184

ABSTRACT

Global pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a ß-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Immunity, Humoral , Influenza A virus/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/virology , Chlorocebus aethiops , Cytomegalovirus/immunology , Dogs , Female , HEK293 Cells , Humans , Immunity, Cellular , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Orthomyxoviridae Infections/virology , Vero Cells
17.
EBioMedicine ; 75: 103762, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1587929

ABSTRACT

BACKGROUND: Vaccines in emergency use are efficacious against COVID-19, yet vaccine-induced prevention against nasal SARS-CoV-2 infection remains suboptimal. METHODS: Since mucosal immunity is critical for nasal prevention, we investigated the efficacy of an intramuscular PD1-based receptor-binding domain (RBD) DNA vaccine (PD1-RBD-DNA) and intranasal live attenuated influenza-based vaccines (LAIV-CA4-RBD and LAIV-HK68-RBD) against SARS-CoV-2. FINDINGS: Substantially higher systemic and mucosal immune responses, including bronchoalveolar lavage IgA/IgG and lung polyfunctional memory CD8 T cells, were induced by the heterologous PD1-RBD-DNA/LAIV-HK68-RBD as compared with other regimens. When vaccinated animals were challenged at the memory phase, prevention of robust SARS-CoV-2 infection in nasal turbinate was achieved primarily by the heterologous regimen besides consistent protection in lungs. The regimen-induced antibodies cross-neutralized variants of concerns. Furthermore, LAIV-CA4-RBD could boost the BioNTech vaccine for improved mucosal immunity. INTERPRETATION: Our results demonstrated that intranasal influenza-based boost vaccination induces mucosal and systemic immunity for effective SARS-CoV-2 prevention in both upper and lower respiratory systems. FUNDING: This study was supported by the Research Grants Council Collaborative Research Fund, General Research Fund and Health and Medical Research Fund in Hong Kong; Outbreak Response to Novel Coronavirus (COVID-19) by the Coalition for Epidemic Preparedness Innovations; Shenzhen Science and Technology Program and matching fund from Shenzhen Immuno Cure BioTech Limited; the Health@InnoHK, Innovation and Technology Commission of Hong Kong; National Program on Key Research Project of China; donations from the Friends of Hope Education Fund; the Theme-Based Research Scheme.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Immunization, Secondary , Influenza Vaccines , SARS-CoV-2 , Vaccines, DNA , Administration, Intranasal , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Disease Models, Animal , Dogs , Female , HEK293 Cells , Humans , Immunity, Mucosal , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Vaccines, DNA/genetics , Vaccines, DNA/immunology , Vero Cells
18.
J Clin Invest ; 131(13)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1556620

ABSTRACT

Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of cross-reactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an egg-produced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine-H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galß1-4GalNAcß), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza.


Subject(s)
Antibodies, Viral/biosynthesis , Influenza Vaccines/immunology , Influenza, Human/immunology , Viral Proteins/immunology , Adult , Age Factors , Aged , Animals , Antibodies, Monoclonal/immunology , Antibodies, Viral/blood , Cohort Studies , Cross Reactions , Eggs/analysis , Humans , Immunoglobulin G/biosynthesis , Immunoglobulin G/blood , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H3N2 Subtype/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , Middle Aged , Polysaccharides/immunology , Vaccination
19.
Front Immunol ; 12: 765528, 2021.
Article in English | MEDLINE | ID: covidwho-1555219

ABSTRACT

Influenza vaccination is an effective public health measure to reduce the risk of influenza illness, particularly when the vaccine is well matched to circulating strains. Notwithstanding, the efficacy of influenza vaccination varies greatly among vaccinees due to largely unknown immunological determinants, thereby dampening population-wide protection. Here, we report that dietary fibre may play a significant role in humoral vaccine responses. We found dietary fibre intake and the abundance of fibre-fermenting intestinal bacteria to be positively correlated with humoral influenza vaccine-specific immune responses in human vaccinees, albeit without reaching statistical significance. Importantly, this correlation was largely driven by first-time vaccinees; prior influenza vaccination negatively correlated with vaccine immunogenicity. In support of these observations, dietary fibre consumption significantly enhanced humoral influenza vaccine responses in mice, where the effect was mechanistically linked to short-chain fatty acids, the bacterial fermentation product of dietary fibre. Overall, these findings may bear significant importance for emerging infectious agents, such as COVID-19, and associated de novo vaccinations.


Subject(s)
Dietary Fiber/pharmacology , Immunity, Humoral/drug effects , Influenza Vaccines/immunology , Influenza, Human/immunology , Adolescent , Adult , Animals , Dietary Fiber/metabolism , Fatty Acids, Volatile/metabolism , Fatty Acids, Volatile/pharmacology , Female , Fermentation , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/immunology , Humans , Immunogenicity, Vaccine , Influenza, Human/microbiology , Influenza, Human/prevention & control , Male , Mice , Middle Aged , Orthomyxoviridae/immunology , Seasons , Vaccination , Young Adult
20.
Nutrients ; 13(12)2021 Dec 02.
Article in English | MEDLINE | ID: covidwho-1551616

ABSTRACT

A single-center, randomized, double-blind, placebo-controlled study was conducted in 72 volunteers who received a synergistic combination of yeast-based ingredients with a unique ß-1,3/1,6-glucan complex and a consortium of heat-treated probiotic Saccharomyces cerevisiae rich in selenium and zinc (ABB C1®) or placebo on the next day after getting vaccinated against influenza (Chiromas®) (n = 34) or the COVID-19 (Comirnaty®) (n = 38). The duration of treatment was 30 and 35 days for the influenza and COVID-19 vaccine groups, respectively. Mean levels of CD4+T cells increased from 910.7 at baseline to 1000.2 cells/µL after the second dose of the COVID-19 vaccine in the ABB C1® group, whereas there was a decrease from 1055.1 to 929.8 cells/µL in the placebo group. Changes of CD3+T and CD8+T lymphocytes showed a similar trend. In the COVID-19 cohort, the increases in both IgG and IgM were higher in the ABB C1® supplement than in the placebo group. Serum levels of selenium and zinc showed a higher increase in subjects treated with the active product than in those receiving placebo. No serious adverse events related to ABB C1® or tolerance issues were reported. The study findings validate the capacity of the ABB C1® product to stimulate trained immunity.


Subject(s)
COVID-19 Vaccines/administration & dosage , Dietary Supplements , Influenza Vaccines/administration & dosage , Saccharomyces cerevisiae , Selenium/administration & dosage , Zinc/administration & dosage , beta-Glucans/administration & dosage , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Double-Blind Method , Female , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Influenza Vaccines/immunology , Male , Middle Aged , Selenium/immunology , Zinc/immunology , beta-Glucans/immunology
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