Understanding influenza transmission,immunity and pandemic threats

Abstract The current pandemic threat can be best understood within an ecological framework that takes account of the history of past pandemics caused by influenza A, the relationships between pandemic and seasonal spread of influenza viruses, and the importance of immunity and behavioural responses in human populations. Isolated populations without recent exposure to seasonal influenza seem more susceptible to new pandemic viruses, and much collateral evidence suggests that this is due to immunity directed against epitopes shared between pandemic and previously circulating strains of inter‐pandemic influenza A virus. In the highly connected modern world, most populations are regularly exposed to non‐pandemic viruses, which can even boost immunity without causing influenza symptoms. Such naturally‐induced immunity helps to explain the low attack‐rates of seasonal influenza, as well as the moderate attack‐rates in many urbanized populations affected by 1918–1919 and later pandemics. The effectiveness of immunity, even against seasonal influenza, diminishes over time because of antigenic drift in circulating viruses and waning of post‐exposure immune responses. Epidemiological evidence suggests that cross‐protection against a new pandemic strain could fade even faster. Nevertheless, partial protection, even of short duration, induced by prior seasonal influenza or vaccination against it, could provide important protection in the early stages of a new pandemic.     

MF59®‐adjuvanted vaccines for seasonal and pandemic influenza prophylaxis

Abstract Influenza is a major cause of worldwide morbidity and mortality through frequent seasonal epidemics and infrequent pandemics. Morbidity and mortality rates from seasonal influenza are highest in the most frail, such as the elderly, those with underlying chronic conditions and very young children. Antigenic mismatch between strains recommended for vaccine formulation and circulating viruses can further reduce vaccine efficacy in these populations. Seasonal influenza vaccines with enhanced, cross‐reactive immunogenicity are needed to address these problems and can confer a better immune protection, particularly in seasons were antigenic mismatch occurs. A related issue for vaccine development is the growing threat of pandemic influenza caused by H5N1 avian strains. Vaccines against strains with pandemic potential offer the best approach for reducing the potential impact of a pandemic. However, current non‐adjuvanted pre‐pandemic vaccines offer suboptimal immunogenicity against H5N1. For both seasonal and pre‐pandemic vaccines, the addition of adjuvants may be the best approach for providing enhanced cross‐reactive immunogenicity. MF59^®, the first oil‐in‐water emulsion licensed as an adjuvant for human use, can enhance vaccine immune responses through multiple mechanisms. A trivalent MF59‐adjuvanted seasonal influenza vaccine (Fluad^®) has shown to induce significantly higher immune responses to influenza vaccination in the elderly, compared with non‐adjuvanted vaccines, and to provide cross‐reactive immunity against divergent influenza strains. Similar results have been generated with a MF59‐adjuvanted H5N1 pre‐pandemic vaccine, which showed higher and broader immunogenicity compared with non‐adjuvanted pre‐pandemic vaccines.     

Universally Immune: How Infection Permissive Next Generation Influenza Vaccines May Affect Population Immunity and Viral Spread

Next generation influenza vaccines that target conserved epitopes are becoming a clinical reality but still have challenges to overcome. Universal next generation vaccines are considered a vital tool to combat future pandemic viruses and have the potential to vastly improve long-term protection against seasonal influenza viruses. Key vaccine strategies include HA-stem and T cell activating vaccines; however, they could have unintended effects for virus adaptation as they recognise the virus after cell entry and do not directly block infection. This may lead to immune pressure on residual viruses. The potential for immune escape is already evident, for both the HA stem and T cell epitopes, and mosaic approaches for pre-emptive immune priming may be needed to circumvent key variants. Live attenuated influenza vaccines have not been immunogenic enough to boost T cells in adults with established prior immunity. Therefore, viral vectors or peptide approaches are key to harnessing T cell responses. A plethora of viral vector vaccines and routes of administration may be needed for next generation vaccine strategies that require repeated long-term administration to overcome vector immunity and increase our arsenal against diverse influenza viruses.     

Targets for the induction of protective immunity against influenza a viruses

The current pandemic caused by the new influenza A(H1N1) virus of swine origin and the current pandemic threat caused by the highly pathogenic avian influenza A viruses of the H5N1 subtype have renewed the interest in the development of vaccines that can induce broad protective immunity. Preferably, vaccines not only provide protection against the homologous strains, but also against heterologous strains, even of another subtype. Here we describe viral targets and the arms of the immune response involved in protection against influenza virus infections such as antibodies directed against the hemagglutinin, neuraminidase and the M2 protein and cellular immune responses directed against the internal viral proteins.     

Hallmarks of CD4 T cell immunity against influenza

The mechanisms responsible for heterosubtypic immunity to influenza virus are not well understood but might hold the key for new vaccine strategies capable of providing lasting protection against both seasonal and pandemic strains. Memory CD4 T cells are capable of providing substantial protection against influenza both through direct effector mechanisms and indirectly through regulatory and helper functions. Here, we discuss the broad impact of memory CD4 T cells on heterosubtypic immunity against influenza and the prospects of translating findings from animal models into improved human influenza vaccines.     

Influenza Viruses Suitable for Studies in Syrian Hamsters

Several small animal models, including mice, Syrian hamsters, guinea pigs, and ferrets are used to study the pathogenicity, transmissibility, and antigenicity of seasonal and pandemic influenza viruses. Moreover, animal models are essential for vaccination and challenge studies to evaluate the immunogenicity and protective efficacy of new vaccines. However, authentic human influenza viruses do not always replicate efficiently in these animal models. Previously, we developed a high-yield A/Puerto Rico/8/34 (PR8-HY) vaccine virus backbone that conferred an increased virus yield to several seasonal influenza vaccines in eukaryotic cells and embryonated chicken eggs. Here, we show that this PR8-HY genetic backbone also increases the replication of several seasonal influenza viruses in Syrian hamsters compared to the authentic viruses. Therefore, the PR8-HY backbone is useful for animal studies to assess the biological properties of influenza viral HA and NA.     

Comparison of a live attenuated 2009 H1N1 vaccine with seasonal influenza vaccines against 2009 pandemic H1N1 virus infection in mice and ferrets

The role of seasonal influenza vaccination in pandemic influenza A H1N1 disease is important to address, because a large segment of the population is vaccinated annually. We administered 1 or 2 doses of pandemic H1N1 vaccine (CA/7 ca), a seasonal trivalent inactivated (s-TIV), or live attenuated influenza vaccine (s-LAIV) to mice and ferrets and subsequently challenged them with a pandemic H1N1 virus. In both species, CA/7 ca was immunogenic and conferred complete protection against challenge. s-TIV did not confer protection in either animal model, and s-LAIV did not confer any protection in ferrets. In mice, 2 doses of s-LAIV led to complete protection in the upper respiratory tract and partial protection in the lungs. Our data indicate that vaccination with the seasonal influenza vaccines did not confer complete protection in the lower respiratory tract in either animal model, whereas the CA/7 ca vaccine conferred complete protection in both animal models.     

Inactivated seasonal influenza vaccines increase serum antibodies to the neuraminidase of pandemic influenza A(H1N1) 2009 virus in an age-dependent manner

Levels of preexisting antibodies to the hemagglutinin of pandemic influenza A(H1N1) 2009 (hereafter pandemic H1N1) virus positively correlate with age. The impact of contemporary seasonal influenza vaccines on establishing immunity to other pandemic H1N1 proteins is unknown. We measured serum antibodies to the neuraminidase (NA) of pandemic H1N1 in adults prior to and after vaccination with seasonal trivalent inactivated influenza vaccines. Serum antibodies to pandemic H1N1 NA were observed in all age groups; however, vaccination elevated levels of pandemic H1N1 NA antibodies predominately in elderly individuals (age, ?60 years). Therefore, contemporary seasonal vaccines likely contribute to reduction of pandemic H1N1-associated disease in older individuals.     

Advances and Future Challenges in Recombinant Adenoviral Vectored H5N1 Influenza Vaccines

The emergence of a highly pathogenic avian influenza virus H5N1 has increased the potential for a new pandemic to occur. This event highlights the necessity for developing a new generation of influenza vaccines to counteract influenza disease. These vaccines must be manufactured for mass immunization of humans in a timely manner. Poultry should be included in this policy, since persistent infected flocks are the major source of avian influenza for human infections. Recombinant adenoviral vectored H5N1 vaccines are an attractive alternative to the currently licensed influenza vaccines. This class of vaccines induces a broadly protective immunity against antigenically distinct H5N1, can be manufactured rapidly, and may allow mass immunization of human and poultry. Recombinant adenoviral vectors derived from both human and non-human adenoviruses are currently being investigated and appear promising both in nonclinical and clinical studies. This review will highlight the current status of various adenoviral vectored H5N1 vaccines and will outline novel approaches for the future.     

Immunization with 1976 swine H1N1- or 2009 pandemic H1N1-inactivated vaccines protects mice from a lethal 1918 influenza infection

Please cite this paper as: Easterbrook et al. (2011) Immunization with 1976 swine H1N1‐ or 2009 pandemic H1N1‐inactivated vaccines protects mice from a lethal 1918 influenza infection. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2010.00191.x. Background Zoonotic infections with H1N1 influenza viruses that evolved initially from the 1918 virus (1918) and adapted to swine threatened a pandemic in 1976 (1976 swH1N1) and a novel reassortant H1N1 virus caused a pandemic in 2009–2010 (2009 pH1N1). Epidemiological and laboratory animal studies show that protection from severe 2009 pH1N1 infection is conferred by vaccination or prior infection with 1976 swH1N1 or 1918. Objectives Our aim was to demonstrate cross‐protection by immunization with 2009 pH1N1 or 1976 swH1N1 vaccines following a lethal challenge with 1918. Further, the mechanisms of cross‐protective antibody responses were evaluated. Methods Mice were immunized with 1976 swH1N1, 2009 pH1N1, 2009 seasonal trivalent, or 1918 vaccines and challenged with 1918. Cross‐reactive antibody responses were assessed and protection monitored by survival, weight loss, and pathology in mice. Results and Conclusions Vaccination with the 1976 swH1N1 or 2009 pH1N1 vaccines protected mice from a lethal challenge with 1918, and these mice lost no weight and had significantly reduced viral load and pathology in the lungs. Protection was likely due to cross‐reactive antibodies detected by microneutralization assay. Our data suggest that the general population may be protected from a future 1918‐like pandemic because of prior infection or immunization with 1976 swH1N1 or 2009 pH1N1. Also, influenza protection studies generally focus on cross‐reactive hemagglutination‐inhibiting antibodies; while hemagglutinin is the primary surface antigen, this fails to account for other influenza viral antigens. Neutralizing antibody may be a better correlate of human protection against pathogenic influenza strains and should be considered for vaccine efficacy.     

Improving seasonal and pandemic influenza vaccines

Abstract Challenges facing seasonal and pandemic influenza vaccination include: increasing the immunogenicity of seasonal vaccines for the most vulnerable, increasing vaccination coverage against seasonal influenza, and developing vaccines against pandemic strains that are immunogenic with very low quantities of antigen to maximize the number of people who can be vaccinated with a finite production capacity. We review Sanofi Pasteur’s epidemic and pandemic influenza research and development programmes with emphasis on two key projects: intradermal influenza vaccine for seasonal vaccination of both elderly and younger adults, and pandemic influenza vaccine.     

Vaccination in adults

The vaccination programme for adults in Germany is based on the comprehensive immunization acquired during childhood and adolescence. The goal of these vaccinations given at regular intervals is to achieve effective immunization coverage lasting into old age. The public health authorities in Germany recommend, according to the Standing Vaccination Commission (STIKO) standards, that adults should receive at least a decennial booster vaccination against diphtheria and tetanus as well as a pertussis booster if the last pertussis vaccine was administered more than 10 years earlier. Individuals above the age of 60 additionally benefit from vaccinations against pneumococcal diseases and annual vaccinations against seasonal influenza. In special life situations, e.g. during pregnancy, vaccination against influenza is also recommended for younger people. The current amendments to the recommendations of the STIKO are aimed at definitive control of measles and eradication of rubella embryopathy. A periodic check-up of the individual vaccination status, and if appropriate completion of missing vaccinations is an important duty of every practising physician. Supporting the creation of herd immunity contributes to the protection of individuals as well as the whole population.     

COVID-19疫苗保护效力及挑战

由严重急性呼吸综合征冠状病毒-2(SARS-CoV-2)感染引起的2019冠状病毒病(COVID-19)为全球流行病,安全、有效的疫苗接种对结束COVID-19流行至关重要.随机临床试验被认为是评价疫苗干预效果的"金标准",但也存在明显局限性.随着全球大规模人群接种COVID-19疫苗,需要在非受控条件下跨越不同人群对...     

Vaccines for seasonal and pandemic influenza

Seasonal influenza continues to have a huge annual impact in the United States, accounting for tens of millions of illnesses, hundreds of thousands of excess hospitalizations, and tens of thousands of excess deaths. Vaccination remains the mainstay for the prevention of influenza. In the United States, 2 types of influenza vaccine are currently licensed: trivalent inactivated influenza vaccine and live attenuated influenza vaccine. Both are safe and effective in the populations for which they are approved for use. Children, adults <65 years of age, and the elderly all receive substantial health benefits from vaccination. In addition, vaccination appears to be cost-effective, if not cost saving, across the age spectrum. Despite long-standing recommendations for the routine vaccination of persons in high-priority groups, US vaccination rates remain too low across all age groups. Important issues to be addressed include improving vaccine delivery to current and expanded target groups, ensuring timely availability of adequate vaccine supply, and development of even more effective vaccines. Development of a vaccine against potentially pandemic strains is an essential part of the strategy to control and prevent a pandemic outbreak. The use of existing technologies for influenza vaccine production would be the most straightforward approach, because these technologies are commercially available and licensing would be relatively simple. Approaches currently being tested include subvirion inactivated vaccines and cold-adapted, live attenuated vaccines. Preliminary results have suggested that, for some pandemic antigens, particularly H5, subvirion inactivated vaccines are poorly immunogenic, for reasons that are not clear. Data from evaluation of live pandemic vaccines are pending. Second-generation approaches designed to provide improved immune responses at lower doses have focused on adjuvants such as alum and MF59, which are currently licensed for influenza or other vaccines. Additional experimental approaches are required to achieve the ultimate goal for seasonal and pandemic influenza prevention--namely, the ability to generate broadly cross-reactive and durable protection in humans.     

IL-15 adjuvanted multivalent vaccinia-based universal influenza vaccine requires CD4+ T cells for heterosubtypic protection

Current influenza vaccines are ineffective against novel viruses and the source or the strain of the next outbreak of influenza is unpredictable; therefore, establishing universal immunity by vaccination to limit the impact of influenza remains a high priority. To meet this challenge, a novel vaccine has been developed using the immunogenic live vaccinia virus as a vaccine vector, expressing multiple H5N1 viral proteins (HA, NA, M1, M2, and NP) together with IL-15 as a molecular adjuvant. Previously, this vaccine demonstrated robust sterile cross-clade protection in mice against H5 influenza viruses, and herein its use has been extended to mediate heterosubtypic immunity toward viruses from both group 1 and 2 HA lineages. The vaccine protected mice against lethal challenge by increasing survival and significantly reducing lung viral loads against the most recent human H7N9, seasonal H3N2, pandemic-2009 H1N1, and highly pathogenic H7N7 influenza A viruses. Influenza-specific antibodies elicited by the vaccine failed to neutralize heterologous viruses and were unable to confer protection by passive transfer. Importantly, heterologous influenza-specific CD4⁺ and CD8⁺ T-cell responses that were elicited by the vaccine were effectively recalled and amplified following viral challenge in the lungs and periphery. Selective depletion of T-cell subsets in the immunized mice revealed an important role for CD4⁺ T cells in heterosubtypic protection, despite low sequence conservation among known MHC-II restricted epitopes across different influenza viruses. This study illustrates the potential utility of our multivalent Wyeth/IL-15/5Flu as a universal influenza vaccine with a correlate of protective immunity that is independent of neutralizing antibodies.Influenza causes widespread infection during seasonal epidemics and occasional worldwide pandemics despite available vaccines. The subtype of future outbreaks or pandemic influenza strains is unpredictable as is its source, evident from the most recent H7N9 outbreak from poultry in China, the variant H3N2 outbreak from swine in the United States in 2012, the H1N1 worldwide pandemic of 2009, and the highly pathogenic avian influenza (HPAI) H5N1 in 1997 from domestic poultry. Therefore, the development of a successful universal vaccination strategy is urgently needed.Universal protection requires heterosubtypic immunity (HSI), whereby vaccination against one influenza virus cross-protects against novel and emerging strains that could potentially be mediated by multiple adaptive immune mechanisms. T cells are potent mediators of HSI, because these cells typically recognize peptide epitopes derived from internal proteins of influenza virus, which are naturally more conserved than surface HA and NA across different strains and even serologically distinct viral subtypes. Because of sequence conservation of the majority of T-cell epitopes between different influenza viruses, cross-reactive T-cell responses have been detected in healthy seronegative individuals against H5N1 and pandemic H1N1-2009 viruses (1, 2).Previously, we generated a multivalent vaccinia virus-based H5N1 influenza vaccine, which demonstrated effective cross-clade immunity against lethal H5N1 challenges. This vaccine expresses five H5N1-derived influenza proteins (HA, NA, M1, M2, and NP), in combination with the immune stimulatory cytokine IL-15 (3) that increases long-term memory responses, along with enhanced T-cell, B-cell, and NK cell functions, including cytokine production and survival. Despite the use of live vaccine vectors being generally constrained in immune-compromised individuals, the vaccine vector (Wyeth/IL-15) has been proven safe and effective in primates and immune-deficient mice (4).A cell-culture–derived, live vaccine vector that encodes full-length influenza proteins with inherent capacity to access MHC-I and II processing pathways to establish robust influenza-specific T-cell responses is an excellent approach to overcome issues related to population-wide MHC polymorphism and egg-based production methods for HPAI vaccines. Herein, we extend the use of Wyeth/IL-15/5Flu vaccine against multiple human influenza viruses of different HA subtypes, including the highly pathogenic H7N7, pandemic H1N1-2009, seasonal H3N2, and the most recent human H7N9 viruses. The vaccine proved effective against all of the heterologous strains tested, and the immunological mechanisms of protection were investigated to decipher correlates of immunity.     

Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus

Development of an influenza vaccine that provides broadly cross-protective immunity has been a scientific challenge for more than half a century. This study presents an approach to overcome strain-specific protection by supplementing conventional vaccines with virus-like particles (VLPs) containing the conserved M2 protein (M2 VLPs) in the absence of adjuvants. We demonstrate that an inactivated influenza vaccine supplemented with M2 VLPs prevents disease symptoms without showing weight loss and confers complete cross protection against lethal challenge with heterologous influenza A viruses including the 2009 H1N1 pandemic virus as well as heterosubtypic H3N2 and H5N1 influenza viruses. Cross-protective immunity was long-lived, for more than 7 mo. Immune sera from mice immunized with M2 VLP supplemented vaccine transferred cross protection to naive mice. Dendritic and macrophage cells were found to be important for this cross protection mediated by immune sera. The results provide evidence that supplementation of seasonal influenza vaccines with M2 VLPs is a promising approach for overcoming the limitation of strain-specific protection by current vaccines and developing a universal influenza A vaccine.     

The Nature of Immune Responses to Influenza Vaccination in High-Risk Populations

The current pandemic has brought a renewed appreciation for the critical importance of vaccines for the promotion of both individual and public health. Influenza vaccines have been our primary tool for infection control to prevent seasonal epidemics and pandemics such as the 2009 H1N1 influenza A virus pandemic. Certain high-risk populations, including the elderly, people with obesity, and individuals with comorbidities such as type 2 diabetes mellitus, are more susceptible to increased disease severity and decreased vaccine efficacy. High-risk populations have unique microenvironments and immune responses that contribute to increased vulnerability for influenza infections. This review focuses on these differences as we investigate the variations in immune responses to influenza vaccination. In order to develop better influenza vaccines, it is critical to understand how to improve responses in our ever-growing high-risk populations.     

Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 pandemic of 1957: an experiment of nature

During a pandemic, influenza vaccines that rely on neutralizing antibodies to protect against matched viruses might not be available early enough. Much broader (heterosubtypic) immune protection is seen in animals. Do humans also have cross-subtype immunity? To investigate this issue, archival records from the Cleveland Family Study, which was conducted before and during the 1957 pandemic (during which a shift from subtype H1N1 to H2N2 occurred), were analyzed. Only 5.6% of the adults who had had symptomatic influenza A in earlier study years developed influenza during the pandemic, despite living in households with participants who had influenza. In contrast, 55.2% of the children who had had symptomatic influenza A contracted it again. These findings suggest an impact of accumulated heterosubtypic immunity during a pandemic. Such immunity, as well as its implications for vaccination, should be further investigated.     

Cross-reactive CD8+ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Preexisting T-cell immunity directed at conserved viral regions promotes enhanced recovery from influenza virus infections, with there being some evidence of cross-protection directed at variable peptides. Strikingly, many of the immunogenic peptides derived from the current pandemic A(H1N1)-2009 influenza virus are representative of the catastrophic 1918 “Spanish flu” rather than more recent “seasonal” strains. We present immunological and structural analyses of cross-reactive CD8⁺ T-cell–mediated immunity directed at a variable (although highly cross-reactive) immunodominant NP_418–426 peptide that binds to a large B7 family (HLA-B*3501/03/0702) found throughout human populations. Memory CD8⁺ T-cell specificity was probed for 12 different NP₄₁₈ mutants that emerged over the 9 decades between the 1918 and 2009 pandemics. Although there is evidence of substantial cross-reactivity among seasonal NP₄₁₈ mutants, current memory T-cell profiles show no preexisting immunity to the 2009-NP₄₁₈ variant or the 1918-NP₄₁₈ variant. Natural infection with the A(H1N1)-2009 virus, however, elicits CD8⁺ T cells specific for the 2009-NP₄₁₈ and 1918-NP₄₁₈ epitopes. This analysis points to the potential importance of cross-reactive T-cell populations that cover the possible spectrum of T-cell variants and suggests that the identification of key residues/motifs that elicit cross-reactive T-cell sets could facilitate the evolution of immunization protocols that provide a measure of protection against unpredicted pandemic influenza viruses. Thus, it is worth exploring the potential of vaccines that incorporate peptide variants with a proven potential for broader immunogenicity, especially to those that are not recognized by the current memory T-cell pool generated by exposure to influenza variants that cause successive seasonal epidemics.     

Influenza Vaccines: A Moving Interdisciplinary Field

Vaccination is by far the most effective way of preventing morbidity and mortality due to infection of the upper respiratory tract by influenza virus. Current vaccines require yearly vaccine updates as the influenza virus can escape vaccine-induced humoral immunity due to the antigenic variability of its surface antigens. In case of a pandemic, new vaccines become available too late with current vaccine practices. New technologies that allow faster production of vaccine seed strains in combination with alternative production platforms and vaccine formulations may shorten the time gap between emergence of a new influenza virus and a vaccine becoming available. Adjuvants may allow antigen-sparing, allowing more people to be vaccinated with current vaccine production capacity. Adjuvants and universal vaccines can target immune responses to more conserved influenza epitopes, which eventually will result in broader protection for a longer time. In addition, further immunological studies are needed to gain insights in the immune features that contribute to protection from influenza-related disease and mortality, allowing redefinition of correlates of protection beyond virus neutralization in vitro.