Direct interaction of whole-inactivated influenza A and pneumococcal vaccines enhances influenza-specific immunity


The upper respiratory tract is continuously exposed to a vast array of potentially pathogenic viruses and bacteria. Influenza A virus (IAV) has particular synergism with the commensal bacterium Streptococcus pneumoniae in this niche, and co-infection exacerbates pathogenicity and causes significant mortality. However, it is not known whether this synergism is associated with a direct interaction between the two pathogens. We have previously reported that co-administration of a whole-inactivated IAV vaccine (γ-Flu) with a whole-inactivated pneumococcal vaccine (γ-PN) enhances pneumococcal-specific responses. In this study, we show that mucosal co-administration of γ-Flu and γ-PN similarly augments IAV-specific immunity, particularly tissue-resident memory cell responses in the lung. In addition, our in vitro analysis revealed that S. pneumoniae directly interacts with both γ-Flu and with live IAV, facilitating increased uptake by macrophages as well as increased infection of epithelial cells by IAV. These observations provide an additional explanation for the synergistic pathogenicity of IAV and S. pneumoniae, as well as heralding the prospect of exploiting the phenomenon to develop better vaccine strategies for both pathogens.

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Fig. 1: Enhanced protection against drifted and heterosubtypic IAV challenge following co-vaccination with γ-Flu + γ-PN(ΔPsaA).
Fig. 2: In vitro neutralization of A/PR8 by vaccine-induced antibodies.
Fig. 3: IAV-specific T-cell populations in peripheral blood and secondary lymphoid organs.
Fig. 4: The magnitude of the IAV-specific CD8+ T-cell response in the lung is enhanced by co-vaccination.
Fig. 5: The presence of γ-PN(ΔPsaA) enhances the uptake of IAV by the THP-1 and MDCK cell lines.
Fig. 6: Direct association of γ-Flu and γ-PN(ΔPsaA) whole-inactivated vaccines.

Data availability

The data that support the findings of this study are available from the corresponding author upon request.


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The authors thank Adelaide University Microscopy (Adelaide, Australia) for assistance in sample preparation and operation of the FEI Tecnai G2 Spirit TEM. We also acknowledge the following funding sources supporting this research: an Australian Institute of Nuclear Science and Engineering (AINSE) Research Award (ALNGRA15517; to M.A.); an Australian Postgraduate Award and Gamma Vaccines Pty Ltd research sponsorship (to S.C.D.); and a National Health and Medical Research Council Senior Principal Research Fellowship (awarded to J.C.P.).

Author information

M.A., S.C.D. and J.C.P. conceived and designed the study. S.C.D., T.N., T.T., J.J.W., E.V.S., Z.L. and J.D. performed the experiments. S.C.D. and T.N. performed statistical analysis. S.C.D. and M.A. wrote the manuscript. T.R.H., I.C. and S.R.M. assisted in experimental design, preparation of the manuscript and provided reagents. M.A. and J.C.P. supervised the study.

Correspondence to Mohammed Alsharifi.

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Competing interests

M.A. is head of the vaccine research group at the University of Adelaide and the Chief Scientific Officer of Gamma Vaccines Pty Ltd and Director of GPN Vaccines Pty Ltd, J.C.P. is a Director of GPN Vaccines Pty Ltd, and T.R.H. is the Executive Chairman of Gamma Vaccines Pty Ltd and GPN Vaccines Pty Ltd. This does not alter adherence to policies on sharing data and materials. Both Gamma Vaccines Pty Ltd and GPN Vaccines Pty Ltd have no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Supplementary Figures 1–3, Tables 1 and 2, and Flow Cytometry Gating Strategies 1–5.

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David, S.C., Norton, T., Tyllis, T. et al. Direct interaction of whole-inactivated influenza A and pneumococcal vaccines enhances influenza-specific immunity. Nat Microbiol 4, 1316–1327 (2019).

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