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Pramila Rijal

DPhil


SENIOR POSTDOCTORAL SCIENTIST

Antibodies and vaccines against influenza virus

VLP BASED VACCINE AGAINST INFLUENZA VIRUS

My last 10 years of experience have been on the isolation and characterization of human monoclonal antibodies to Influenza and Ebola viruses. I have also been helping with the development of the in-house S-FLU, a live-attenuated influenza vaccine, and the assessment of influenza monoclonal antibodies in pigs (collaboration with Dr Elma Tchilian, Pirbright Institute). 

Recently we isolated and characterized broadly cross-reactive antibodies to neuraminidase. We reported three monoclonal antibodies originating from vaccinated or infected human individuals which had cross-reactivity to NAs that spanned 100 years of evolution. One antibody cross-reacted with neuraminidases of different subtypes belonging to two different genetic groups (1). Structural analysis showed that this antibody recognized the catalytic site of neuraminidase (2). We also showed that these antibodies can protect against virus infection in a mouse model. 

The very broad reactivity of these human monoclonal antibodies contrasts with the narrow reactivity of polyclonal sera to neuraminidase (1). This suggests the variable regions of the neuraminidase tend to be immunodominant. With this new insight that broadly cross-reactive and protective antibodies to neuraminidase exist, we are aiming to target the vaccine response to the conserved epitopes. Our approach involves the display of recombinant neuraminidase protein on the surface of virus-like particles (VLP) facilitated by Spycatcher technology. We have shown that it is possible to display trimeric hemagglutinin and tetrameric neuraminidase on the surface of a porous dodecahedral VLP nanocage formed by 60 subunits of engineered mi3 (bacterial KDPG aldolase) protein. NA-SpyVLP particles elicited a strong enzyme NA-inhibiting antibody response with the low dose of 0.1 µg protein (3). We have recently expanded our experience with this technology by applying it to COVID-19 (4) .

We want to explore if it is possible to elicit a broadly reactive anti neuraminidase polyclonal response to the epitopes defined by our monoclonal antibodies by tailoring the VLP vaccine. Our crystal structures show that the footprint of the cross-reactive monoclonals lies within a single monomeric subunit of the tetramer. We also know that many less cross-reactive antibodies bind to combinatorial epitopes formed at the highly variable interface of monomers within the tetramer. We have recently demonstrated that isolated monomers express well, and retain the conserved epitope seen by a cross-reactive monoclonal. We now will form a VLP coated in pure monomers with the aim of focusing the antibody response on the conserved epitopes within the monomer.  We will further expand this vaccine scope by also studying avian neuraminidase, co-displaying hemagglutinin and neuraminidase, immunising particles as admixtures or mosaics. We have a PhD student Ms Leiyan Wei since 2020 funded by the CAMS to work on this project.

1.         Rijal P, Wang BB, Tan TK, Schimanski L, Janesch P, Dong T, McCauley JW, Daniels RS, Townsend AR, Huang KA. 2020. Broadly Inhibiting Antineuraminidase Monoclonal Antibodies Induced by Trivalent Influenza Vaccine and H7N9 Infection in Humans. J Virol 94.

2.         Jiang H, Peng W, Qi J, Chai Y, Song H, Bi Y, Rijal P, Wang H, Oladejo BO, Liu J, Shi Y, Gao GF, Townsend AR, Wu Y. 2020. Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus. mBio 11.

3.         Rahikainen R, Rijal P, Tan TK, Wu HJ, Andersson AC, Barrett JR, Bowden TA, Draper SJ, Townsend AR, Howarth M. 2021. Overcoming Symmetry Mismatch in Vaccine Nanoassembly through Spontaneous Amidation. Angew Chem Int Ed Engl 60:321-330.

4.         Tan TK, Rijal P, Rahikainen R, Keeble AH, Schimanski L, Hussain S, Harvey R, Hayes JWP, Edwards JC, McLean RK, Martini V, Pedrera M, Thakur N, Conceicao C, Dietrich I, Shelton H, Ludi A, Wilsden G, Browning C, Zagrajek AK, Bialy D, Bhat S, Stevenson-Leggett P, Hollinghurst P, Tully M, Moffat K, Chiu C, Waters R, Gray A, Azhar M, Mioulet V, Newman J, Asfor AS, Burman A, Crossley S, Hammond JA, Tchilian E, Charleston B, Bailey D, Tuthill TJ, Graham SP, Duyvesteyn HME, Malinauskas T, Huo J, Tree JA, Buttigieg KR, Owens RJ, Carroll MW, Daniels RS, McCauley JW, et al. 2021. A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses. Nat Commun 12:542.