scholarly journals Review of Influenza Virus Vaccines: The Qualitative Nature of Immune Responses to Infection and Vaccination Is a Critical Consideration

Vaccines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 979
Author(s):  
Lily Chan ◽  
Kasra Alizadeh ◽  
Kimia Alizadeh ◽  
Fatemeh Fazel ◽  
Julia E. Kakish ◽  
...  

Influenza viruses have affected the world for over a century, causing multiple pandemics. Throughout the years, many prophylactic vaccines have been developed for influenza; however, these viruses are still a global issue and take many lives. In this paper, we review influenza viruses, associated immunological mechanisms, current influenza vaccine platforms, and influenza infection, in the context of immunocompromised populations. This review focuses on the qualitative nature of immune responses against influenza viruses, with an emphasis on trained immunity and an assessment of the characteristics of the host–pathogen that compromise the effectiveness of immunization. We also highlight innovative immunological concepts that are important considerations for the development of the next generation of vaccines against influenza viruses.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.


Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 793
Author(s):  
Ying Huang ◽  
Monique S. França ◽  
James D. Allen ◽  
Hua Shi ◽  
Ted M. Ross

Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive antigens (COBRAs) in the form of recombinant hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1 vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA vaccine, two new candidate COBRA HA vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013–2019. In this study, the effectiveness of COBRA Y2 and Y4 vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA vaccines. Mice vaccinated with the next generation COBRA HA vaccines effectively protected against morbidity and mortality after infection with H1N1 influenza viruses. The antibodies elicited by the COBRA HA vaccines were highly cross-reactive with influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection.


mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Z. Beau Reneer ◽  
Amanda L. Skarlupka ◽  
Parker J. Jamieson ◽  
Ted M. Ross

ABSTRACT Influenza vaccines have traditionally been tested in naive mice and ferrets. However, humans are first exposed to influenza viruses within the first few years of their lives. Therefore, there is a pressing need to test influenza virus vaccines in animal models that have been previously exposed to influenza viruses before being vaccinated. In this study, previously described H2 computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) vaccines (Z1 and Z5) were tested in influenza virus “preimmune” ferret models. Ferrets were infected with historical, seasonal influenza viruses to establish preimmunity. These preimmune ferrets were then vaccinated with either COBRA H2 HA recombinant proteins or wild-type H2 HA recombinant proteins in a prime-boost regimen. A set of naive preimmune or nonpreimmune ferrets were also vaccinated to control for the effects of the multiple different preimmunities. All of the ferrets were then challenged with a swine H2N3 influenza virus. Ferrets with preexisting immune responses influenced recombinant H2 HA-elicited antibodies following vaccination, as measured by hemagglutination inhibition (HAI) and classical neutralization assays. Having both H3N2 and H1N1 immunological memory regardless of the order of exposure significantly decreased viral nasal wash titers and completely protected all ferrets from both morbidity and mortality, including the mock-vaccinated ferrets in the group. While the vast majority of the preimmune ferrets were protected from both morbidity and mortality across all of the different preimmunities, the Z1 COBRA HA-vaccinated ferrets had significantly higher antibody titers and recognized the highest number of H2 influenza viruses in a classical neutralization assay compared to the other H2 HA vaccines. IMPORTANCE H1N1 and H3N2 influenza viruses have cocirculated in the human population since 1977. Nearly every human alive today has antibodies and memory B and T cells against these two subtypes of influenza viruses. H2N2 influenza viruses caused the 1957 global pandemic and people born after 1968 have never been exposed to H2 influenza viruses. It is quite likely that a future H2 influenza virus could transmit within the human population and start a new global pandemic, since the majority of people alive today are immunologically naive to viruses of this subtype. Therefore, an effective vaccine for H2 influenza viruses should be tested in an animal model with previous exposure to influenza viruses that have circulated in humans. Ferrets were infected with historical influenza A viruses to more accurately mimic the immune responses in people who have preexisting immune responses to seasonal influenza viruses. In this study, preimmune ferrets were vaccinated with wild-type (WT) and COBRA H2 recombinant HA proteins in order to examine the effects that preexisting immunity to seasonal human influenza viruses have on the elicitation of broadly cross-reactive antibodies from heterologous vaccination.


Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 133 ◽  
Author(s):  
Magen E. Francis ◽  
Mara McNeil ◽  
Nicholas J. Dawe ◽  
Mary K. Foley ◽  
Morgan L. King ◽  
...  

Influenza virus imprinting is now understood to significantly influence the immune responses and clinical outcome of influenza virus infections that occur later in life. Due to the yearly cycling of influenza viruses, humans are imprinted with the circulating virus of their birth year and subsequently build a complex influenza virus immune history. Despite this knowledge, little is known about how the imprinting strain influences vaccine responses. To investigate the immune responses of the imprinted host to split-virion vaccination, we imprinted ferrets with a sublethal dose of the historical seasonal H1N1 strain A/USSR/90/1977. After a +60-day recovery period to build immune memory, ferrets were immunized and then challenged on Day 123. Antibody specificity and recall were investigated throughout the time course. At challenge, the imprinted vaccinated ferrets did not experience significant disease, while naïve-vaccinated ferrets had significant weight loss. Haemagglutination inhibition assays showed that imprinted ferrets had a more robust antibody response post vaccination and increased virus neutralization activity. Imprinted-vaccinated animals had increased virus-specific IgG antibodies compared to the other experimental groups, suggesting B-cell maturity and plasticity at vaccination. These results should be considered when designing the next generation of influenza vaccines.


2008 ◽  
Vol 15 (7) ◽  
pp. 1042-1053 ◽  
Author(s):  
Bruce D. Forrest ◽  
Michael W. Pride ◽  
Andrew J. Dunning ◽  
Maria Rosario Z. Capeding ◽  
Tawee Chotpitayasunondh ◽  
...  

ABSTRACT The highly sensitive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 107 fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children.


2015 ◽  
Vol 22 (8) ◽  
pp. 957-964 ◽  
Author(s):  
Karen L. Laurie ◽  
Othmar G. Engelhardt ◽  
John Wood ◽  
Alan Heath ◽  
Jacqueline M. Katz ◽  
...  

ABSTRACTThe microneutralization assay is commonly used to detect antibodies to influenza virus, and multiple protocols are used worldwide. These protocols differ in the incubation time of the assay as well as in the order of specific steps, and even within protocols there are often further adjustments in individual laboratories. The impact these protocol variations have on influenza serology data is unclear. Thus, a laboratory comparison of the 2-day enzyme-linked immunosorbent assay (ELISA) and 3-day hemagglutination (HA) microneutralization (MN) protocols, using A(H1N1)pdm09, A(H3N2), and A(H5N1) viruses, was performed by the CONSISE Laboratory Working Group. Individual laboratories performed both assay protocols, on multiple occasions, using different serum panels. Thirteen laboratories from around the world participated. Within each laboratory, serum sample titers for the different assay protocols were compared between assays to determine the sensitivity of each assay and were compared between replicates to assess the reproducibility of each protocol for each laboratory. There was good correlation of the results obtained using the two assay protocols in most laboratories, indicating that these assays may be interchangeable for detecting antibodies to the influenza A viruses included in this study. Importantly, participating laboratories have aligned their methodologies to the CONSISE consensus 2-day ELISA and 3-day HA MN assay protocols to enable better correlation of these assays in the future.


Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1399 ◽  
Author(s):  
Jianzhou Cui ◽  
Dhakshayini Morgan ◽  
Dao Han Cheng ◽  
Sok Lin Foo ◽  
Gracemary L. R. Yap ◽  
...  

Influenza viruses have been shown to use autophagy for their survival. However, the proteins and mechanisms involved in the autophagic process triggered by the influenza virus are unclear. Annexin-A1 (ANXA1) is an immunomodulatory protein involved in the regulation of the immune response and Influenza A virus (IAV) replication. In this study, using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR associated protein 9) deletion of ANXA1, combined with the next-generation sequencing, we systematically analyzed the critical role of ANXA1 in IAV infection as well as the detailed processes governing IAV infection, such as macroautophagy. A number of differentially expressed genes were uniquely expressed in influenza A virus-infected A549 parental cells and A549 ∆ANXA1 cells, which were enriched in the immune system and infection-related pathways. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed the role of ANXA1 in autophagy. To validate this, the effect of mechanistic target of rapamycin (mTOR) inhibitors, starvation and influenza infection on autophagy was determined, and our results demonstrate that ANXA1 enhances autophagy induced by conventional autophagy inducers and influenza virus. These results will help us to understand the underlying mechanisms of IAV infection and provide a potential therapeutic target for restricting influenza viral replication and infection.


2020 ◽  
pp. 1-5
Author(s):  
Venkata dinesh kumar kandula

● At first haemophilus influenza was considered as the causative agent for influenza but after the research it has been found that it caused various other types of infections but not influenza. Influenza was caused by some flu virus which was first isolated from pigs in 1931 and from humans in 1933.(4) ● The 1918 influenza pandemic was the most severe pandemic in recent history it was caused by an H1N1 virus with the genes of avian origin although there is not universal consensus regarding where the virus originated it spread worldwide during 1918 and 1919. (3) ● It was first identified in military personnel in spring 1980 it is estimated that about 500 million people or one third of the world's population became infected with this virus.(3) ● The number of deaths was estimated to be at least 50 million worldwide with about 6,75,000 deaths occurring in the United States. (3) ● Mortality was high in people younger than five years old ,20 to 40 years old and in 65 years and older. The high mortality in healthy people including those in the 20 to 40 year age group was a unique feature of this pandemic. (3) ● There was no vaccine to protect against influenza infection and no antibiotics to treat secondary bacterial infections that can be associated with influenza infection control efforts worldwide were limited to non-pharmaceutical intervention such as isolation quarantine good personal hygiene use of disinfectants and limitations of public gathering which were applied unevenly.(3) ● In the northern and southern parts of the world outbreaks occur mainly in the winter while around the equator outbreaks may occur at any time of the year .In the northern and southern parts of the world outbreaks occur mainly in the winter while around the equator outbreaks may occur at any time of the year.(7) ● In the 20th century three influenza pandemics occurred Spanish influenza in 1918 where the death toll ranged from 17- 200 million deaths, Asian influenza in 1957- 2 million deaths and Hong Kong influenza in 1968 -1 million deaths. ● The world health organisation declared an outbreak of a new type of influenza A or H1N1 to be a pandemic in June 2009. ● influenza may also affect other animals including pig horses and birds.(9) ● The name “influenza” originated in 15th century Italy, from an epidemic attributed to “influence of the stars.” The first pandemic that fits the description of influenza was in 1580. At least four pandemics of influenza occurred in the 19th century, and three occurred in the 20th century. The pandemic of “Spanish” influenza in 1918–1919 caused an estimated 21 million deaths worldwide. The first pandemic of the 21st century occurred in 2009–2010. Historically, influenza viruses of three HA subtypes (H1, H2 and H3) have acquired the ability to be transmitted efficiently between humans. Currently, influenza viruses of the H1 and H3 subtype co-circulate in humans, however influenza viruses of the H2, H5, H6, H7 and H9 subtype are also considered to represent a pandemic threat. In 1997, a large outbreak of highly pathogenic avian influenza (HPAI) H5N1 virus in poultry in Hong Kong resulted in the first documented cases of direct transmission of HPAI H5N1 virus from poultry to humans, with a fatal outcome in 6 out of 18 cases [17]. As a result, this outbreak warranted the mass culling of 1.5 million chickens. In 2003, a large outbreak of an HPAI H7N7 virus in poultry in the Netherlands resulted in 89 cases of human infections, one of which was fatal [21]. HPAI H7N7 virus displayed an unusual tissue tropism; the virus targeted the conjunctiva, resulting in conjunctivitis, a symptom rarely reported for other influenza virus subtypes.(1)


2018 ◽  
Vol 7 (4) ◽  
pp. 113-120
Author(s):  
Darja Kanduc

Abstract Autoantibodies (AAbs) against von Willebrand factor (vWF)-cleaving protease ADAMTS13 causally relate to thrombotic thrombocytopenic purpura (TTP). How anti-ADAMTS13 AAbs are generated is unknown. Starting from reports according to which influenza infection can trigger TTP by the production of ADAMTS13 AAbs, this study explores influenza viruses and ADAMTS13 protein for common peptide sequences that might underlie anti-influenza immune responses able to cross-react with ADAMTS13. Results document that numerous peptides are shared between influenza A and B viruses and ADAMTS13, thus supporting the hypothesis of cross-reactivity as a mechanism driving the generation of anti-ADAMTS13 AAbs.


2020 ◽  
Author(s):  
Yaron Drori ◽  
Jasmine Jacob-Hirsch ◽  
Rakefet Pando ◽  
Aharona Glatman-Freedman ◽  
Nehemya Friedman ◽  
...  

AbstractInfluenza viruses and respiratory syncytial virus (RSV) are respiratory viruses that primarily circulate worldwide during the autumn and winter seasons. Seasonal surveillance shows that RSV infection generally precedes influenza. However, in the last four winter seasons (2016-2020) an overlap of the morbidity peaks of both viruses was observed in Israel, and was paralleled by significantly lower RSV infection rates. To investigate whether the influenza virus inhibits RSV we performed coinfection of Human cervical carcinoma (HEp2) cells or mice with influenza and RSV and we observed that the influenza inhibited RSV growth, both in vitro and in vivo. Mass spectrometry analysis of mouse lungs infected with influenza identified a two-wave pattern of protein expression upregulation, which included members of the interferon-induced protein with tetratricopeptide (IFITs) family. Interestingly, in the second peak of upregulation, influenza viruses were no longer detectable in mouse lungs. We also observed that knockdown and overexpression of IFITs in HEp2 cells affected RSV multiplicity. In conclusion, influenza infection inhibits RSV infectivity via upregulation of IFIT proteins in a two-wave modality. Understanding of the interaction between influenza and RSV viruses and immune system involvement will contribute to the development and optimization of future treatment strategies against these viruses.Author SummaryRespiratory syncytial virus (RSV) and influenza viruses are both respiratory viruses associated with morbidity and mortality worldwide. RSV is usually detected in October, with a clear peak in December, whereas influenza virus arrives in November and peaks in January. In the last four seasons, influenza infection overlapped with that of RSV in Israel, which resulted in decreased morbidity of RSV suggesting that influenza virus inhibits RSV infection. To identify the mechanism responsible for the influenza inhibition of RSV we performed experiments in culture and in mice. We observed that influenza infection results in two wave modality of inhibition of RSV infection. Using mass spectrometry perfornmed on lungs from infected mice we show that influenza infection induces the expression of (IFIT) family of proteins which also showed a two-wave modality. Using knockdown and overexpression experiments we showed that indeed the IFTIs inhibits RSV infection. Our study provides new insights on the interaction between influenza and RSV viruses and immune system involvement and contribute to the development of future treatment strategies against these viruses.


Sign in / Sign up

Export Citation Format

Share Document