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Immune Prophylaxis Targeting the Respiratory Syncytial Virus (RSV) G Protein
Harrison C Bergeron1, Jackelyn Murray1, Aakash Arora1
1Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
Insights
Two new antibodies targeting the respiratory syncytial virus (RSV) G protein, 2D10 and 3D3, show distinct therapeutic potentials. 2D10 neutralizes RSV prophylactically and therapeutically, while 3D3 reduces viral load and inflammation.
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- Respiratory Syncytial Virus (RSV) causes significant respiratory illness in infants and the elderly.
- Current prophylaxis, palivizumab, targets the RSV fusion (F) protein but doesn't address pathogenic responses from the attachment (G) protein.
- Two novel high-affinity anti-G protein monoclonal antibodies (mAbs), 3D3 and 2D10, bind distinct epitopes on the G protein's central conserved domain (CCD).
Purpose of the Study:
- To evaluate and compare the neutralization and immunomodulatory effects of anti-G protein mAbs 3D3 and 2D10 against RSV Line19F infection in a mouse model.
- To assess the prophylactic and therapeutic efficacy of 3D3 and 2D10 in reducing RSV disease and associated immune responses.
Main Methods:
- Mouse models were infected with RSV Line19F to mimic human RSV infection.
- Mice received prophylactic (24h prior) or therapeutic (72h post) treatment with mAbs 3D3, 2D10, palivizumab, or isotype control.
- Viral titers and cytokine levels (e.g., IL-13) in lung tissue were analyzed to assess treatment efficacy.
Main Results:
- mAb 2D10 demonstrated both prophylactic and therapeutic neutralization of RSV Line19F, reducing disease-causing immune responses only in the prophylactic setting.
- mAb 3D3 significantly reduced lung virus titers and IL-13 levels in both prophylactic and therapeutic treatment regimens.
- Distinct epitopes targeted by 3D3 and 2D10 result in subtle but important differences in immune responses to RSV infection.
Conclusions:
- Both anti-G protein mAbs, 3D3 and 2D10, offer potential for RSV immunoprophylaxis and therapy, exhibiting different efficacy profiles.
- The study highlights the importance of targeting the RSV G protein for a comprehensive immune response against RSV.
- Further research into the distinct mechanisms of action of mAbs binding different G protein epitopes is warranted for optimized RSV treatment strategies.
Abstract:
The respiratory syncytial virus (RSV) causes significant respiratory disease in young infants and the elderly. Immune prophylaxis in infants is currently limited to palivizumab, an anti-RSV fusion (F) protein monoclonal antibody (mAb). While anti-F protein mAbs neutralize RSV, they are unable to prevent aberrant pathogenic responses provoked by the RSV attachment (G) protein. Recently, the co-crystal structures of two high-affinity anti-G protein mAbs that bind the central conserved domain (CCD) at distinct non-overlapping epitopes were solved. mAbs 3D3 and 2D10 are broadly neutralizing and block G protein CX3C-mediated chemotaxis by binding antigenic sites γ1 and γ2, respectively, which is known to reduce RSV disease. Previous studies have established 3D3 as a potential immunoprophylactic and therapeutic; however, there has been no similar evaluation of 2D10 available. Here, we sought to determine the differences in neutralization and immunity to RSV Line19F infection which recapitulates human RSV infection in mouse models making it useful for therapeutic antibody studies. Prophylactic (24 h prior to infection) or therapeutic (72 h post-infection) treatment of mice with 3D3, 2D10, or palivizumab were compared to isotype control antibody treatment. The results show that 2D10 can neutralize RSV Line19F both prophylactically and therapeutically, and can reduce disease-causing immune responses in a prophylactic but not therapeutic context. In contrast, 3D3 was able to significantly (p < 0.05) reduce lung virus titers and IL-13 in a prophylactic and therapeutic regimen suggesting subtle but important differences in immune responses to RSV infection with mAbs that bind distinct epitopes.
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