LETTER
Computationally optimized broadly reactive antigens (COBRA) designed for different influenza virus subtypes (H1N1, H3N2, and H5N1) elicit a subtype-specific broad antibody (Ab) response in naive as well as in preimmune influenza virus animal models (1–9).
In particular, an H1 hemagglutinin (HA) COBRA candidate, named P1, has been designed by a multiple-sequence alignment of HA sequences belonging to H1 swine and human strains (1). Importantly, immunization with P1 elicits a broad neutralizing Ab response against H1 human and swine viruses (1, 4, 10).
Recently, we generated a panel of P1-specific mouse monoclonal Abs (MAbs) with the aim to dissect the Ab response to P1. As previously described, these MAbs feature different functional activities, spanning from narrowly to broadly reactive against H1N1 human viruses (11).
In this study, we investigated the breadth of hemagglutination inhibition (HAI) featured by representative P1-elicited MAbs along with those generated following immunization with wild-type historic H1N1 human vaccine strains in order to dissect the breadth of HAI activity of the P1-elicited response against influenza swine viruses.
As shown in Fig. 1A, P1-specific MAbs featured a differentiating breadth of HAI activity, spanning from narrowly to broadly reactive against H1N1, H1N2, and H2N3 swine viruses. Interestingly, MAbs endowed with broad HAI activity against a panel of human H1N1 viruses featured a narrower HAI profile against swine viruses. Comparatively, those endowed with a narrower profile against human viruses featured a broader profile against swine viruses belonging to the Eurasian, classical, and human seasonal-like lineages (11).
FIG 1.
HAI and neutralizing activity breadth of P1- (A), seasonal-, and pandemic-specific (B) MAbs against influenza A H1N1, H1N2, and H2N3 swine viruses.
Unsurprisingly, due to its swine origin, CA/09-specific MAbs, previously classified to have a narrow profile of neutralization activity against pandemic and pandemic-like viruses (11), collectively exhibited a broad HAI activity against H1N1 and H1N2 swine viruses and none against the A/Swine/Missouri/4296424/2006 H2N3 virus (Fig. 1B).
Interestingly, a P1-specific MAb (4C5), previously demonstrated to have no HAI activity against any of the human H1N1 strains (11), showed detectable HAI activity against H1N1 and H1N2 swine viruses, suggesting that its epitope is particular to swine viruses and not to human seasonal, pandemic, and pandemic-like HA proteins.
The antigenic cartography segregates MAbs based on their HAI profile against human and swine viruses, with the P1 and pandemic-specific MAbs clustering together as opposed to the seasonal (Brisb/07)-specific MAbs (Fig. 2) (11, 12). However, further investigation aimed at determining the amino acid contact residues of these MAbs will improve the resolution of the recognized epitopes, clarify distinctions between human- and swine-specific H1 epitopes, and elucidate the mechanism of breadth conferred by COBRA immunogens.
FIG 2.
Antigenic cartography map of P1-, seasonal-, and pandemic-specific MAbs. Map was drawn based on the minimum HAI concentration from this and previous studies (11).
ACKNOWLEDGMENTS
The MAbs 5D3, 6B9, 39E4, IC5-4F8, RA5-22, 1C5, 5C12, CA09-02, CA09-09, CA09-11, and CA09-15 were obtained from the Biodefense and Emerging Infections (BEI) Resources Repository while AT170.558.146, AT170.119.5, AT163.272.54, AT163.210.182, AT163.333.93, AT163.104.93, AT163.329.189 MAbs were obtained from the Influenza Reagent Resource (IRR).
The A/North Carolina/152702/2015, A/North Carolina/02744/2009, A/Illinois/02860/2009, A/Minnesota/02751/2009, A/Missouri/A01444664/2013, A/Swine/1931, A/Utah/02861/2009, and A/Nebraska/A01444614/2013 viruses were kindly provided by S. Mark Tompkins, Ralph Tripp (University of Georgia), and the Minnesota Veterinary Diagnostic Laboratory (University of Minnesota). Finally, we thank Silvia Carnaccini for helpful discussions.
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