title: A replication-defective human cytomegalovirus vaccine for prevention of congenital infection.
abstract: Congenital human cytomegalovirus (HCMV) infection occurs in ~0.64% of infants born each year in the United States and is the leading nongenetic cause of childhood neurodevelopmental disabilities. No licensed HCMV vaccine is currently available. Natural immunity to HCMV in women before pregnancy is associated with a reduced risk of fetal infection, suggesting that a vaccine is feasible if it can reproduce immune responses elicited by natural infection. On the basis of this premise, we developed a whole-virus vaccine candidate from the live attenuated AD169 strain, with genetic modifications to improve its immunogenicity and attenuation. We first restored the expression of the pentameric gH/gL/pUL128-131 protein complex, a major target for neutralizing antibodies in natural immunity. We then incorporated a chemically controlled protein stabilization switch in the virus, enabling us to regulate viral replication with a synthetic compound named Shield-1. The virus replicated as efficiently as its parental virus in the presence of Shield-1 but failed to produce progeny upon removal of the compound. The vaccine was immunogenic in multiple animal species and induced durable neutralizing antibodies, as well as CD4+and CD8+T cells, to multiple viral antigens in nonhuman primates.
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA. dai_wang@merck.com tong-ming_fu@merck.com.
authors: Dai
authors: D
authors: Wang
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Daniel C
authors: DC
authors: Freed
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Xi
authors: X
authors: He
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Fengsheng
authors: F
authors: Li
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Aimin
authors: A
authors: Tang
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Kara S
authors: KS
authors: Cox
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Sheri A
authors: SA
authors: Dubey
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Suzanne
authors: S
authors: Cole
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Muneeswara Babu
authors: MB
authors: Medi
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Yaping
authors: Y
authors: Liu
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Jingyuan
authors: J
authors: Xu
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Zhi-Qiang
authors: ZQ
authors: Zhang
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Adam C
authors: AC
authors: Finnefrock
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Liping
authors: L
authors: Song
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Amy S
authors: AS
authors: Espeseth
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: John W
authors: JW
authors: Shiver
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors: Danilo R
authors: DR
authors: Casimiro
authors: Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA. dai_wang@merck.com tong-ming_fu@merck.com.
authors: Tong-Ming
authors: TM
authors: Fu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000151:congenital* / Q000517:prevention & control*; D022482:Cytomegalovirus Vaccines / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000071497:Immunogenicity, Vaccine; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D011817:Rabbits; D014613:Vaccines, Attenuated / Q000627:therapeutic use; D014764:Viral Proteins / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D014613:Vaccines, Attenuated; D014764:Viral Proteins; D007371:Interferon-gamma