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. 2016 Sep 22:7:12838.
doi: 10.1038/ncomms12838.

A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques

Sujin Lee  1   2 , Minh Trang Nguyen  1   2 , Michael G Currier  1   2 , Joe B Jenkins  3 , Elizabeth A Strobert  3 , Adriana E Kajon  4 , Ranjna Madan-Lala  5 , Yury A Bochkov  6 , James E Gern  6   7 , Krishnendu Roy  5 , Xiaoyan Lu  8 , Dean D Erdman  8 , Paul Spearman  1   2 , Martin L Moore  1   2
Affiliations

A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques

Sujin Lee et al. Nat Commun. .

Abstract

As the predominant aetiological agent of the common cold, human rhinovirus (HRV) is the leading cause of human infectious disease. Early studies showed that a monovalent formalin-inactivated HRV vaccine can be protective, and virus-neutralizing antibodies (nAb) correlated with protection. However, co-circulation of many HRV types discouraged further vaccine efforts. Here, we test the hypothesis that increasing virus input titres in polyvalent inactivated HRV vaccine may result in broad nAb responses. We show that serum nAb against many rhinovirus types can be induced by polyvalent, inactivated HRVs plus alhydrogel (alum) adjuvant. Using formulations up to 25-valent in mice and 50-valent in rhesus macaques, HRV vaccine immunogenicity was related to sufficient quantity of input antigens, and valency was not a major factor for potency or breadth of the response. Thus, we have generated a vaccine capable of inducing nAb responses to numerous and diverse HRV types.

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Conflict of interest statement

M.L.M. co-founded and serves as Chief Scientific Officer for Meissa Vaccines, Inc. S.L., M.T.N. and M.L.M are co-inventors in a patent application (PCT/US2016/037658) describing the rhinovirus vaccine reported in this paper. The vaccine technology has been optioned to Meissa Vaccines, Inc. by Emory University. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Immunogenicity of inactivated HRV is not affected by increasing valency from one to ten.
Mice were vaccinated i.m. with 1-valent inactivated HRV-16 with or without alum adjuvant (5 mice per group) or with 3-valent, 5-valent, 7-valent or 10-valent inactivated HRV with alum (20 mice per group). HRV types and inactivated-TCID50 doses are specified in Supplementary Table 1. Sera were collected 18 days after vaccination and pooled for each group. Serum nAb titres were measured against HRV-16, HRV-36 and HRV-78. The dashed line represents limit of detection (LOD). Error bars show 95% confidence interval. Data depict three independent experiments combined.
Figure 2
Figure 2. Immunogenicity of inactivated polyvalent HRV is related to dose.
Mice (2 groups, 20 per group) were vaccinated with 10-valent HRV vaccine consisting of low inactivated-TCID50 per dose input titres (x-axis), similar to the 1975 Hamory et al. study, plus alum (magenta open circles) or with 10-valent HRV vaccine with high inactivated-TCID50 per dose input titres plus alum (blue open squares). Sera were collected 18 days after prime (a) and 18 days after boost (b), pooled for each group and nAb titres (y-axis) were measured against the indicated types in the vaccines. The dashed line represents LOD. Undetectable nAb were assigned LOD/2, and some symbols below LOD were nudged for visualization. Three independent experiments using low input titres showed similar results. There was a statistically significant association between input TCID50 virus titre and a detectable nAb response following prime (P=0.01) and boost (P=0.03) vaccination (Fisher's exact test).
Figure 3
Figure 3. Broad nAb responses against 10-valent and 25-valent inactivated HRV in mice.
The inactivated-TCID50 input titres per dose are specified in Supplementary Table 2. (a) 20 mice were vaccinated then boosted at 50 days with 10-valent HRV. (b) 30 mice were vaccinated then boosted at 50 days with 25-valent HRV. Sera were collected at day 18 (prime) and day 68 (boost). nAb levels against the indicated types in the vaccines were measured in pooled sera. Error bars depict 95% confidence interval. Data shown represent one of three (10-valent) or two (25-valent) experiments with similar results. The dashed line represents LOD. Undetectable nAb were assigned LOD/2.
Figure 4
Figure 4. Broad nAb responses against 25-valent and 50-valent inactivated HRV in RMs.
The inactivated-TCID50 input titres per dose are specified in Supplementary Table 3. Two RMs (RM A and RM B) were vaccinated i.m. with 25-valent HRV and alum (a,b), and two RMs (RM C and RM D) were vaccinated i.m. with 50-valent HRV and alum (c,d). nAb titres against input virus types were measured in individual serum samples collected at day 18 (a,c). The RM received an identical boost vaccination at day 28, and sera were collected at day 46 for determining nAb titres post-boost vaccination (b,d). Error bars depict 95% confidence interval. The dashed line represents LOD. Undetectable nAb were assigned LOD/2.
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References

    1. Gwaltney J. M. Jr, Hendley J. O., Simon G. & Jordan W. S. Jr Rhinovirus infections in an industrial population. I. The occurrence of illness. N. Engl. J. Med. 275, 1261–1268 (1966). - PubMed
    1. Glanville N. & Johnston S. L. Challenges in developing a cross-serotype rhinovirus vaccine. Curr. Opin. Virol. 11, 83–88 (2015). - PubMed
    1. Jain S. et al.. Community-acquired pneumonia requiring hospitalization among U.S. adults. N. Engl. J. Med. 373, 415–427 (2015). - PMC - PubMed
    1. Jain S. et al.. Community-acquired pneumonia requiring hospitalization among U.S. children. N. Engl. J. Med. 372, 835–845 (2015). - PMC - PubMed
    1. Barclay W. S., al-Nakib W., Higgins P. G. & Tyrrell D. A. The time course of the humoral immune response to rhinovirus infection. Epidemiol. Infect. 103, 659–669 (1989). - PMC - PubMed