In the present study, we have shown that macaques are effectively protected from intratracheal challenge with wild-type MV 1 year after vaccination with MVA-FH irrespective of the presence of passively transferred homologous MV-specific antibody. These experiments were carried out with a macaque model for MV infection, with which the same parameters had been previously studied upon vaccination with MV-Schwarz, rVV-FH, and MV-iscom by using essentially the same regimen (26
). The level of passively transferred homologous MV-specific antibodies used was also identical and corresponded to levels of serum VN antibodies that in epidemiological studies have been shown to interfere with the outcome of measles vaccination of infants (2
). These levels relate to serum antibody levels that may be expected in infants of 6 to 9 months of age. In a cohort of 160 Sudanese infants aged about 6 months, we found levels below 0.1 IU/ml in 22% (n
= 35), levels between 0.1 and 0.2 IU/ml in 45% (n
= 72), and levels above 0.2 IU/ml in 33% (n
= 53) of the cohort (unpublished data). This level had been shown to completely abolish the induction of MV-specific antibodies by MV-Schwarz vaccination and almost completely abolish the induction of this response by rVV-FH vaccination (26
). In contrast, a candidate MV-iscom vaccine was shown to induce high titers of MV-specific serum antibody both in the presence and absence of passively transferred homologous MV-specific antibody (26
). In the present study, MVA-FH was shown to induce higher levels of MV-specific antibodies than rVV-FH when administered in the presence of passively transferred neutralizing antibodies. We hypothesize that this is related to the relatively high MVA-FH doses used for vaccination (1 × 106.2
PFU per animal for rVV-FH versus 1 × 108
PFU per animal for MVA-FH). For safety reasons (15
), lower doses of rVV-FH had been administered in the previous experiment (26
). The level of VN antibodies present at the time of the second vaccination (about 0.1 IU/ml; Fig. ), which may at least in part be attributed to the passive immunization, has been shown to interfere with the replication of MV (26
). The serological data also showed that the vaccinia virus-specific immune response induced by the first MVA-FH vaccination did not have a major impact on the immunogenicity of the second vaccination: it did not prevent a clear booster effect in the serological responses against either MV or MVA (Fig. , , and ). Eight weeks after the second vaccination, all the vaccinated macaques showed a pronounced MV-specific T-cell response, as evidenced by MV-specific induction of CD69 expression by CD3+
and of CD3+
bulk cultured cells (Fig. ). This observation is of particular interest since in previous experiments we have shown that also in the absence of MV-neutralizing antibodies, vaccinated macaques may still be largely protected from challenge MV infection, indicating a protective effect of thus induced specific T-cell responses (26
One year after vaccination, all the macaques were intratracheally challenged with MV-BIL (1
). All the vaccinated macaques proved to be effectively protected from MV infection. Only low cell-associated virus loads could be demonstrated in lung lavages and peripheral blood, whereas, as expected, full-blown infection was demonstrated in the MVA-wt sham-vaccinated macaques. The increase in MV-neutralizing as well as F- and H-protein-specific antibody levels after challenge observed in all the macaques, and the induction of N-protein specific IgM antibodies in five of the six vaccinated macaques, confirmed that in all the vaccinated macaques, low-level virus replication had still occurred upon challenge.
Collectively, our data show that vaccination with MVA-FH in a two-dose intramuscular-intranasal regimen in the presence of passively acquired MV-neutralizing antibodies induces long-lasting protective immunity against challenge with wild-type MV. In previous experiments this was also achieved with MV-iscom, but not with live attenuated measles vaccine (MV-Schwarz), or with low doses of rVV-FH (Table ). A clear advantage of MVA-FH over rVV-FH is its documented safety profile, since we have recently shown that even in severely immunosuppressed macaques neither virus replication nor any adverse effects occurred upon MVA infection (Stittelaar et al., submitted for publication). Furthermore, our data suggest that MVA-FH may be used to boost low levels of vaccine-induced immunity more efficiently than live attenuated MV vaccine. This could become of major importance during the final stages of the MV eradication campaign.
TABLE 1 Average VN antibody titers in vaccinatedmacaques
Finally, it is important to note that a live nonreplicating vaccine candidate such as MVA-FH may not be expected to be associated with immunopathological phenomena like the atypical measles syndrome associated with the use of inactivated MV vaccines (7
). We conclude that our data favor the further exploration of the value of MVA-FH as a candidate replication-deficient vaccine as an alternative to the present vaccine for infants with maternally acquired MV-neutralizing antibody and for adults with waning vaccine-induced immunity.