Horizontal Transmission of Cytomegalovirus in a Rhesus Model Despite High-Level, Vaccine-Elicited Neutralizing Antibody and T-Cell Responses

Abstract

The development of a vaccine to prevent congenital human cytomegalovirus (HCMV) disease is a public health priority. We tested rhesus CMV (RhCMV) prototypes of HCMV vaccine candidates in a seronegative macaque oral challenge model. Immunogens included a recombinant pentameric complex (PC; gH/gL/pUL128/pUL130/pUL131A), a postfusion gB ectodomain, and a DNA plasmid that encodes pp65-2. Immunization with QS21-adjuvanted PC alone or with the other immunogens elicited neutralizing titers comparable to those elicited by RhCMV infection. Similarly, immunization with all three immunogens elicited pp65-specific cytotoxic T cell responses comparable to those elicited by RhCMV infection. RhCMV readily infected immunized animals and was detected in saliva, blood and urine after challenge in quantities similar to those in placebo-immunized animals. If HCMV evades vaccine-elicited immunity in humans as RhCMV evaded immunity in macaques, a HCMV vaccine must elicit immunity superior to, or different from, that elicited by the prototype RhCMV vaccine to block horizontal transmission.

Horizontal transmission of endemic viruses among rhesus macaques (Macaca mulatta): Implications for human cytomegalovirus vaccine/challenge design

“…The homologous vaccine/challenge method was used because another study demonstrated that plasma from monkeys inoculated with either of two RhCMV strains exhibiting genetic drift in the coding regions for gB and some of those forming the PC (UCD52 and UCD56) do not cross‐neutralize the other non‐homologous strain 67 . The simplest interpretation of the absence of protective efficacy in the vaccine/oral challenge results in this study 66 is that despite high levels of antiviral immunity in the periphery circulating antiviral immunity is not operative at the oral mucosa, the site of RhCMV challenge. This putative scenario leads directly to two intertwined hypothetical scenarios.…”

“…There are multiple genetic/antigenic variants circulating in NHP at large breeding facilities. 66,67,70,71 Further, prior infection with endemic strains of RhCMV does not appear to restrict iatrogenic reinfections with RhCMV variants. [72][73][74][75][76][77] While RhCMV has been demonstrated to be fully capable of transplacental transmission following iatrogenic inoculation (intravenous), 42 there have been no reports of non-iatrogenic instances of congenital sequelae in neonatal or spontaneously aborted macaques.…”

“…Further, does the mechanistic basis for the reduction in shedding correlate with an increased resistance to reinfection across a mucosal surface? 66 However, while reduction in shedding could conceivably be immunological in nature, the age-related decline in shedding could also be due solely or inter-dependently with viral and/or physiologic determinants. Age-related declines in shedding may reflect that there is a progressively smaller selective benefit to shedding as animals…”

“…Juvenile macaques vaccinated against RhCMV glycoprotein B (gB), phosphoprotein 65, and the gH‐anchored pentameric complex (PC) essential for epithelial/endothelial cell tropism develop levels of antigen‐specific immune responses comparable in levels to those detected in naturally infected animals 66 . However, the vaccinees exhibited no protection against viral acquisition, viremia, or shedding in saliva and urine compared to placebo controls following an oral mucosa challenge model designed to recapitulate natural infection.…”

“…Because of prolonged shedding beyond the 1.5 years necessary to achieve 100% seroprevalence, sexually mature female macaques (≥4–5 years) would undoubtedly be repeatedly exposed to RhCMV. There are multiple genetic/antigenic variants circulating in NHP at large breeding facilities 66,67,70,71 . Further, prior infection with endemic strains of RhCMV does not appear to restrict iatrogenic reinfections with RhCMV variants 72–77 .…”