An MCMV mutant lacking the IFN antagonist pM27 elicits strong humoral immune responses and can serve as a live attenuated vaccine

Human cytomegalovirus (HCMV) frequently causes congenital infections, resulting in birth
defects and developmental disorders. A vaccine is needed, but currently unavailable. We
analysed the potential of an MCMV mutant, lacking its STAT2 antagonists to serve as live
attenuated vaccine in mice. Infections with ΔM27-MCMV confirmed its capability for inducing
ELISA IgG responses in terms of IgG recognizing MCMV-encoded proteins present in infected
cells. For persistent infection, very strong MCMV-specific ELISA-reactive IgG responses were
also mounted. After implementing ELISA on MCMV virions, ΔM27-MCMV induced strong
IgG responses in terms of IgG recognizing MCMV virions. The ΔM27-MCMV was capable to
raise FcγRIII [CD16], FcγRI [CD64], FcγRII [CD32] and FcγRIV activating IgG responses in
BALB/c and C57BL/6 mice. FcγRI, FcγRII and FcγRIII have reached their maximum level of
IgG activation upon infection with ΔM27-MCMV at 14 and 21 days post infection,
respectively. It is likely that ΔM27-MCMV activating IgG responses recognize receptors
expressed on the surface of already infected cells, thereby activating FcγR-expressing
monocytes, macrophages or NK cells, to kill the infected cells through ADCC. Infections with
ΔM27-MCMV induced neutralizing antibodies.
BALB/c and C57BL/6 mice immunized with ΔM27-MCMV resisted the challenge infection
with the MCMV:eGFP (21 and 6 weeks post infection), suggesting that the MCMV deletion
mutant lacking interferon antagonist (ΔM27-MCMV) provides an innate immune stimuli that
influence the effectiveness of the adaptive immune response, resulting in protection from
subsequent challenge infections. To exclude that this leads to exaggerated protection, e.g., due
to an attenuation caused by introduction of the eGFP gene, the ΔM27-MCMV vaccination is
repeated, challenged with wt-MCMV and observed full protection of ΔM27-MCMVimmunized
mice against wt-MCMV challenge. We compared the neutralizing antibody
responses to ΔM27-MCMV 5 weeks post immunization and 3 weeks post challenge infection,
showing that ΔM27-MCMV induces neutralization antibodies that might have influence on
protection from subsequent infections. Nevertheless, antibodies that elicits ΔM27-MCMV are
capable of activating FcγRIII and FcγRIV receptors 5 weeks post infection. Irrespective of the
infection dose, salivary gland viral titers of all BALB/c mice immunized with ΔM27-MCMV
have been below detection limit (102 PFU), therefore suggesting that all immunized mice were
ΔM27-MCMV was able to efficiently protect immunocompetent mice against challenge with
MCMV:eGFP after vaccination with a single dose. Remarkably, vaccination with ΔM27-
MCMV was as efficient as vaccination for long-term protection.


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