A Replication-Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection

Yaping Liu, Daniel C. Freed, Leike Li, Aimin Tang, Fengsheng Li, Edward M. Murray, Stuart P. Adler, Michael A. McVoy, Richard E. Rupp, Diane Barrett, Xiaohua Ye, Ningyan Zhang, Karen Beck, Timothy Culp, Rituparna Das, Liping Song, Kalpit Vora, Hua Zhu, Dai Wang, Amy S. EspesethZhiqiang An, Luwy Musey, Tong Ming Fu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Human cytomegalovirus (HCMV) can cause congenital infections, which are a leading cause of childhood disabilities. Since the rate of maternal-fetal transmission is much lower in naturally infected (HCMV-seropositive) women, we hypothesize that a vaccine candidate capable of eliciting immune responses analogous to those of HCMV-seropositive subjects may confer protection against congenital HCMV. We have previously described a replication-defective virus vaccine based on strain AD169 (D. Wang, D. C. Freed, X. He, F. Li, et al., Sci Transl Med 8:362ra145, 2016, https://doi.org/10.1126/scitranslmed.aaf9387). The vaccine, named V160, has been shown to be safe and immunogenic in HCMV-seronegative human subjects, eliciting both humoral and cellular immune responses (S. P. Adler, S. E. Starr, S. A. Plotkin, S. H. Hempfling, et al., J Infect Dis 220:411-419, 2019, https://doi.org/10.1093/infdis/171.1.26). Here, we further showed that sera from V160-immunized HCMV-seronegative subjects have attributes similar in quality to those from seropositive subjects, including high-avidity antibodies to viral antigens, coverage against a panel of genetically distinct clinical isolates, and protection against viral infection in diverse types of human cells in culture. More importantly, vaccination appeared efficient in priming the human immune system, inducing memory B cells in six V160 recipients at frequencies comparable to those of three HCMV-seropositive subjects. Our results demonstrate the ability of V160 to induce robust and durable humoral memory responses to HCMV, justifying further clinical evaluation of the vaccine against congenital HCMV.IMPORTANCEIn utero HCMV infection can lead to miscarriage or childhood disabilities, and an effective vaccine is urgently needed. Since children born to women who are seropositive prior to pregnancy are less likely to be affected by congenital HCMV infection, it has been hypothesized that a vaccine capable of inducing an immune response resembling the responses in HCMV-seropositive women may be effective. We previously described a replication-defective virus vaccine that has been demonstrated safe and immunogenic in HCMV-seronegative subjects. Here, we conducted additional analyses to show that the vaccine can induce antibodies with functional attributes similar to those from HCMV-seropositive subjects. Importantly, vaccination can induce long-lived memory B cells at frequencies comparable to those seen in HCMV-seropositive subjects. We conclude that this vaccine is a promising candidate that warrants further clinical evaluation for prevention of congenital HCMV.

Original languageEnglish (US)
JournalJournal of virology
Volume93
Issue number23
DOIs
StatePublished - Dec 1 2019

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Cytomegalovirus Vaccines
Human herpesvirus 5
Humoral Immunity
humoral immunity
Cytomegalovirus
vaccines
Infection
infection
Vaccines
Defective Viruses
virus replication
childhood
Cytomegalovirus Infections
B-lymphocytes
vaccination
immune response
Vaccination
B-Lymphocytes

Keywords

  • CMV
  • humoral immunity
  • memory
  • neutralization
  • V160
  • vaccine

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

A Replication-Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection. / Liu, Yaping; Freed, Daniel C.; Li, Leike; Tang, Aimin; Li, Fengsheng; Murray, Edward M.; Adler, Stuart P.; McVoy, Michael A.; Rupp, Richard E.; Barrett, Diane; Ye, Xiaohua; Zhang, Ningyan; Beck, Karen; Culp, Timothy; Das, Rituparna; Song, Liping; Vora, Kalpit; Zhu, Hua; Wang, Dai; Espeseth, Amy S.; An, Zhiqiang; Musey, Luwy; Fu, Tong Ming.

In: Journal of virology, Vol. 93, No. 23, 01.12.2019.

Research output: Contribution to journalArticle

Liu, Y, Freed, DC, Li, L, Tang, A, Li, F, Murray, EM, Adler, SP, McVoy, MA, Rupp, RE, Barrett, D, Ye, X, Zhang, N, Beck, K, Culp, T, Das, R, Song, L, Vora, K, Zhu, H, Wang, D, Espeseth, AS, An, Z, Musey, L & Fu, TM 2019, 'A Replication-Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection', Journal of virology, vol. 93, no. 23. https://doi.org/10.1128/JVI.00747-19
Liu, Yaping ; Freed, Daniel C. ; Li, Leike ; Tang, Aimin ; Li, Fengsheng ; Murray, Edward M. ; Adler, Stuart P. ; McVoy, Michael A. ; Rupp, Richard E. ; Barrett, Diane ; Ye, Xiaohua ; Zhang, Ningyan ; Beck, Karen ; Culp, Timothy ; Das, Rituparna ; Song, Liping ; Vora, Kalpit ; Zhu, Hua ; Wang, Dai ; Espeseth, Amy S. ; An, Zhiqiang ; Musey, Luwy ; Fu, Tong Ming. / A Replication-Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection. In: Journal of virology. 2019 ; Vol. 93, No. 23.
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T1 - A Replication-Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection

AU - Liu, Yaping

AU - Freed, Daniel C.

AU - Li, Leike

AU - Tang, Aimin

AU - Li, Fengsheng

AU - Murray, Edward M.

AU - Adler, Stuart P.

AU - McVoy, Michael A.

AU - Rupp, Richard E.

AU - Barrett, Diane

AU - Ye, Xiaohua

AU - Zhang, Ningyan

AU - Beck, Karen

AU - Culp, Timothy

AU - Das, Rituparna

AU - Song, Liping

AU - Vora, Kalpit

AU - Zhu, Hua

AU - Wang, Dai

AU - Espeseth, Amy S.

AU - An, Zhiqiang

AU - Musey, Luwy

AU - Fu, Tong Ming

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Human cytomegalovirus (HCMV) can cause congenital infections, which are a leading cause of childhood disabilities. Since the rate of maternal-fetal transmission is much lower in naturally infected (HCMV-seropositive) women, we hypothesize that a vaccine candidate capable of eliciting immune responses analogous to those of HCMV-seropositive subjects may confer protection against congenital HCMV. We have previously described a replication-defective virus vaccine based on strain AD169 (D. Wang, D. C. Freed, X. He, F. Li, et al., Sci Transl Med 8:362ra145, 2016, https://doi.org/10.1126/scitranslmed.aaf9387). The vaccine, named V160, has been shown to be safe and immunogenic in HCMV-seronegative human subjects, eliciting both humoral and cellular immune responses (S. P. Adler, S. E. Starr, S. A. Plotkin, S. H. Hempfling, et al., J Infect Dis 220:411-419, 2019, https://doi.org/10.1093/infdis/171.1.26). Here, we further showed that sera from V160-immunized HCMV-seronegative subjects have attributes similar in quality to those from seropositive subjects, including high-avidity antibodies to viral antigens, coverage against a panel of genetically distinct clinical isolates, and protection against viral infection in diverse types of human cells in culture. More importantly, vaccination appeared efficient in priming the human immune system, inducing memory B cells in six V160 recipients at frequencies comparable to those of three HCMV-seropositive subjects. Our results demonstrate the ability of V160 to induce robust and durable humoral memory responses to HCMV, justifying further clinical evaluation of the vaccine against congenital HCMV.IMPORTANCEIn utero HCMV infection can lead to miscarriage or childhood disabilities, and an effective vaccine is urgently needed. Since children born to women who are seropositive prior to pregnancy are less likely to be affected by congenital HCMV infection, it has been hypothesized that a vaccine capable of inducing an immune response resembling the responses in HCMV-seropositive women may be effective. We previously described a replication-defective virus vaccine that has been demonstrated safe and immunogenic in HCMV-seronegative subjects. Here, we conducted additional analyses to show that the vaccine can induce antibodies with functional attributes similar to those from HCMV-seropositive subjects. Importantly, vaccination can induce long-lived memory B cells at frequencies comparable to those seen in HCMV-seropositive subjects. We conclude that this vaccine is a promising candidate that warrants further clinical evaluation for prevention of congenital HCMV.

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KW - CMV

KW - humoral immunity

KW - memory

KW - neutralization

KW - V160

KW - vaccine

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