Delineating the role of CD4+ T cells in the activation of human cytomegalovirus-specific immune responses following immunization with Ad-gBCMVpoly vaccine: implications for vaccination of immunocompromised individuals

Abstract

Reconstitution of the virus-specific CD8 + T-cell response is crucial for the prevention of human cytomegalovirus (CMV)-associated pathogenesis in transplant patients and human immunodeficiency virus-infected individuals. Although adoptive T-cell immunotherapy has been used successfully in various clinical settings, prophylactic vaccination remains the most amenable strategy to prevent CMV disease. However, vaccination in clinical settings where the host is severely immunocompromised due to the loss of CD4 + T cells remains a significant challenge. This study investigated the efficacy of a chimeric CMV vaccine in a model setting that allowed studies on the generation of CD8 + T-cell memory responses in a transient CD4 + T-cell-deficient setting similar to that seen in immunocompromised patients. Immunization with an adenoviral CMV vaccine under transient helpless (complete CD4 + T-cell depletion) or help-deficient (partial CD4 + T-cell depletion) conditions demonstrated that induction of the effector CD8 + T-cell and humoral responses was almost completely eliminated under helpless conditions, and was gradually regained with the recovery of CD4 + T cells. However, this response failed to protect the host from viral infection, suggesting that lack of CD4 + T cells during vaccination can significantly impair the priming and maturation of CMV-specific immune responses. Furthermore, although the induction of CMV-specific immune responses was also significantly reduced in a help-deficient environment, these primed effector cells could mature normally and generate long-term polyfunctional memory responses capable of restricting virus replication in vivo. These results highlight the importance of monitoring CD4 + T-cell numbers before vaccination for the successful implementation of a CMV vaccine in an immunocompromised setting.

Progress toward Development of a Vaccine against Congenital Cytomegalovirus Infection

“…This platform has been developed by the Queensland Institute (121). This vaccine encodes a truncated form of gB antigen and multiple CMV T cell epitopes from eight different CMV antigens.…”

Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

“…While CMV pp65-specific CD8 T cell responses were detected in most C infants and P adults in our study, the frequencies of these responses, particularly single MIP1β- or CD107-expressing and polyfunctional cells, were lower in infants. In adults, polyfunctional T cells are associated with anti-viral protection measured by slower disease progression, more frequent control of viral replication, or reduced antiviral drug treatment [30-32], and measurement of these responses has been used to evaluate anti-viral vaccine strategies [13, 33-36]. Few studies have examined polyfunctional CD4 or CD8 T cell responses in infants, which were detected infrequently in congenital HIV infection [65, 66], but commonly and with heterogeneous phenotype and functional profiles following Bacillus Calmette-Guérin vaccination [35, 67].…”

“…In turn, limited CD4 T cell help and/or amplified T cell suppression may lead to suboptimal generation or maintenance of virus-specific CD8 T cells. In humans and animal models, CD8 T cells generated with inadequate CD4 T cell help during infection or vaccination fail to sustain anti-viral effector function or protection [13, 36, 72]. In addition, T cell functional impairment or “exhaustion” is a distinct molecular state associated with chronic viral infection, which involves expression of inhibitory co-receptors such as programmed death receptor-1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA4), reduced effector functions and proliferative capacity, and relatively terminal differentiation, and correlates with markers of disease progression [53].…”

“…Another strategy is to vaccinate infants with congenital CMV infection as immunotherapy with or without antiviral agents, which has been the basis of CMV vaccine clinical trials in seropositive women or stem cell transplant recipients [6, 9, 10]. Such approaches require that the candidate vaccine induce potent CMV-specific neutralizing antibodies and/or cell-mediated immune responses in infants that correlate with control of viral replication or protection from disease, persist in long-term memory, and are evaluable in clinical trials [11-13]. Moreover, these responses must continuously adapt to the large diversity and rapid evolution of CMV populations within distinct host tissue compartments [14].…”

“…Among other markers, antigen-experienced T cells can be distinguished by expression patterns of the transmembrane phosphatase CD45 isoform and the lymph node homing molecule CCR7 [29]. Moreover, increasing evidence suggests that T cells capable of multiple simultaneous anti-viral effector functions are associated with markers of protection [30-32], and that analysis of these polyfunctional memory T cells may be used to evaluate outcome following vaccination [13, 33-36]. …”