The properties of rLCMV suggest that it holds promise as a vector for vaccination and immunotherapy in infectious diseases and cancer. Its desirable features stem mainly from three properties: (i) its ability to target and functionally activate DCs, (ii) its stimulation of potent CD8+
T cell responses and (iii) its relative insensitivity to antibody neutralization and thus its efficacy in homologous prime-boost vaccination. A cardinal aspect of rLCMV immunogenicity is its targeting to DCs, followed by activation of these cells20
, which is probably responsible for the potent CTL induction. The ability of rLCMV-immunized mice to respond to homologous boosting reflects the poor induction of neutralizing antibodies, an intrinsic feature of the LCMV envelope glycoprotein8
. In addition, the limited number of rLCMV vector particles administered for vaccination here provided relatively low amounts of LCMV-GP, and exposure of the immune system to LCMV-GP was of short duration. The gene encoding LCMV-GP is absent from rLCMV vectors, and the vaccine cannot produce further LCMV-GP in vivo
to trigger GP-specific neutralizing antibody responses. Moreover, even antibodies that potently neutralize LCMV in vitro
exhibit only a limited capacity to interfere with T cell induction in vivo24
. Together these considerations probably explain why even multiple administrations of rLCMV over prolonged periods of time have failed to elicit antibodies that interfere with vector immunogenicity. In addition to the limited interference by preexisting humoral immunity, all the existing evidence suggests that human seroprevalence to LCMV is generally below 5% (refs. 25–28
). In contrast, high-titer protective neutralizing antibody responses are generated to the transgene encoded by the vector, which indicates its likely utility as a vaccine vector in humans. Wild-type LCMV can replicate and cause disease in immunosuppressed transplant recipients29
. The lack of rLCMV replication suggests therefore that these vectors will provide a suitable safety profile for further development in humans.
Possible applications for rLCMV include protective vaccines, for example, against HIV, hepatitis C virus, tuberculosis and malaria, as well as cancer immunotherapy. Preliminary data in mice suggest that rLCMV vectors elicit CD8+ T cell responses to HIV antigens at high frequency and functionality (L.F. and G.J.N., unpublished data). Future studies should determine whether rLCMV vectors are particularly advantageous in eliciting CD8+ T cell responses to self antigens on tumors, in which immunotherapy can be compromised by T cell tolerance.
The choice of an optimal vaccine vector depends on both the properties of the vector and the mechanisms of protection for specific diseases. Additional parameters, including ease of storage, large-scale manufacturing, cost effectiveness and the size of the gene payload, can be limiting and remain to be determined for rLCMV. We have generated rLCMV vectors carrying foreign genes up to 2.6 kilobases in size without technical difficulties. If size limits for inserts existed, multiple vectors carrying individual antigens could be combined in a single vaccine, as successfully performed with recombinant adeno-virus 5–based vectors30
. Given all of these observations, rLCMV represents an attractive vector for stimulating both cellular and humoral immunity. Thus, it provides a platform that may be used to prevent or treat malignant and infectious diseases for which existing vaccination strategies have yet to confer protection.