Broadly protective influenza vaccines for pandemic preparedness Suresh Mittal Department of Comparative Pathobiology Purdue University
Influenza A Virus Orthomyxovirus Consist of s/s (-) sense RNA 8 segments Encodes 11 proteins Subbarao and Jospeh, Nature Reviews Immunology, 2007
Transmission to other species Human flu Natural Reservoirs Aquatic birds Equine flu Avian flu Feline flu Asymptomatic infection Swine flu Other mammals
http://www.ifpma.org/in dex.php?id=4166
Influenza A virus subtypes Nabel and Fauci, Nature Medicine, 2010
Antigenic shift http://www.ifpma.org/index.php?id=4172
2009 H1N1 Influenza pandemic virus Published by AAAS J. Cohen Science 325, 140-141 (2009)
Influenza pandemics
Influenza A Virus infections in humans Main subtypes: H1N1, H1N2, H2N2, H3N2 Viruses currently circulating: H1N1 and H3N2 - H2N2 circulated from about 1957-1968 Responsible for seasonal epidemics and four major influenza pandemics
Avian Influenz A Virus Main subtypes: H5, H7, and H9 H5N1,H7N2,H7N3,H7N7,H9N2 Endemic in domestic poultry in various countries H5, H9: Asia, Africa, and Europe H7 : Europe, North America, and Australia Avian influenza A viruses represent a major threat
World Health Organization http://www.who.int/influenza/
H5N1 infection in humans 622 cases of human infection 371 death Mortality rate: 59.6% 0.1% (1957 and 1968 pandemics) 2.5% (1918 pandemic)
H5N1: Divergent clades Divergent clades Clade1 Clade2 Antigenicity & transmissibility Challenge: Vaccine development
Human Infections with Avian influenza A Viruses- Receptor Specificity Barrier??? Human influenza A viruses infect nonciliated cells (receptors having α2-6 linked sialic acid) Avian influenza A viruses infect ciliated cells (receptors having α2-3 linked sialic acid)
Outbreaks of Avian Influenza in Humans Good News: Human-to-human transmission infrequent Bad News: Avian influenza A viruses evolving rapidly Matter of time before any of these avian viruses gain potential to convert into pandemic strain - Efficient transmission in humans - No immunity
http://en.wikipedia.org /wiki/file:reversegen eticsflu.jpg
Science, 2012
The price of a pandemic 730,000 hospitalizations 42 million outpatient visits 50 million additional illnesses Approx. 200,000 deaths Approx. total cost $166.5 billion
An Ideal Pandemic vaccine Universal influenza vaccine As per WHO estimates we are 5-10 years away from developing such a vaccine A broadly protective vaccine which offers some level of cross-protection within a subtype
Pandemic influenza vaccine requirements Stockpiling option Egg-independent approach Adjuvant-independent (preferred)
Advantages of adenoviral vectors as a vaccine delivery system Non-pathogenic Grown to high titers Availability of certified cell lines Availability of technology for large scale purification No integration into the host genome Targets macrophages and DCs Induce both humoral and CMI responses Effectively delivered by mucosal or parental route Egg-independent approach No need for high containment
Hemagglutinin stem- a major target for crossneutralizing antibodies against influenza A viruses Broadly neutralizing mabs containing epitopes in the conserved HA stem region C179 CR6261 CR8020 F10 F16 12D1 13D4 6F1 LAH CR6261 12D1 CR6261 and 12D1 mabs recognize linear epitopes in the long alpha helix (LAH) portion of stem Wang et al., PNAS, 2010 Ekiert et al., Science, 2009
Nucleoprotein (NP) Multifunctional internal protein - Encapsulates the viral RNA - Plays an important role in virus infection cycle vrna NP Highly conserved across influenza A viruses Potential target for induction of broad protective immunity against influenza viruses
Acknowledgement Purdue University Sai Vikram Vemula Annemarie Swaim Yadvinder Singh Ahi Omar Ahmed Neetu Singh Aseem Pandey CDC Suryaprakash Sambhara Jacqueline Katz Ruben Donis Funding: NIAID
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