In this prospective study, only one-third of antiretroviral-naïve HIV-1-infected Kenyan children with a history of prior measles vaccination had protective titers of measles antibody, a rate comparable to that reported in some studies and lower in others4,12,13
. One explanation for low rates of measles seropositivity despite prior vaccination is that children in this cohort had advanced HIV disease, with a median CD4 percent of 6.3% and median HIV-1 viral load of 1,000,000 copies/ml. All children were infected via mother-to-child HIV-1 transmission and had progressed to clinical AIDS before enrollment into the study. Recruitment into this study involved identification of clinically ill children, thus our results reflect typical pediatric HIV clinic attendees who may be sicker than infants identified via prevention of mother-to-child transmission of HIV-1 programs.
Lack of measles antibody for children with advanced HIV disease may be because of failed induction after initial vaccination or of loss of measles-specific antibody responses over time with progressive HIV disease. Other studies would suggest that it is a combination of these two factors11
. We did not observe measles-specific IgM responses 2 weeks following re-vaccination, suggesting children had previously been exposed to measles. In addition, approximately 40% of children who were measles antibody negative at enrollment converted to measles antibody positive status after immune reconstitution, which would be consistent with prior immunity. However, 60% of children did not convert after HAART and a large proportion (53%) of children who were initially measles IgG positive reverted to antibody negative status during the 6-month follow-up period. For tetanus, change in status from positive to negative was statistically significant, with 15 (31%) of 49 losing tetanus antibody on HAART. Other studies have also found defective humoral immunity among children on HAART and possible explanations include slow functional recovery of B-cell memory and a shorter life-span of plasma cells in HIV-infected children25
. Regardless of the underlying mechanism, HAART alone was not sufficient to restore immune responses in this study and re-vaccination was necessary for a significant number of children.
There may be significant public health implications of these findings. As a result of the decreased ability of HIV-1-infected children to generate and maintain protective vaccine-induced immunity, a growing number of vulnerable children may compromise the World Health Organization’s Expanded Program on Immunizations. In past years, increased vaccine failure among HIV-1-infected children would have been offset by high mortality in this population. However, with the increased accessibility of HAART around the world, and in sub-Saharan Africa in particular, HIV-1 infected children will have extended life expectancies, and could potentially have a greater impact on measles epidemics. This makes it even more important to assess the impact of HAART on immunity against routine childhood immunizations in order to develop appropriate immunization strategies to optimize vaccination.
In contrast to measles immune responses which were present in a minority of children at baseline, the majority (>75%) had positive tetanus IgG antibody titers at enrollment. This is consistent with data showing that cellular immune compromise adversely impacts measles but not tetanus vaccine responses26
. While the humoral response is of paramount importance for vaccine-induced protection against both measles and tetanus, cellular immunity is critically important for mounting a measles vaccine response26
, as demonstrated by studies among immunosuppressed individuals vaccinated against measles showing compromised and more transient responses9
. The fact that tetanus vaccine is first administered during the first 2 months of life whereas measles vaccine is administered at 9 months of age may also contribute to the differential responses. More children are infected with HIV-1 by 9 months, with many experiencing severe immune dysfunction that may not have been present earlier.
All children demonstrated immune reconstitution following 6 months of HAART, with increased CD4 percentage, decreased viral loads, and improved z-score measurements. However, no clinical or immunologic markers were found to be significantly associated with either baseline or 6-month vaccine immune status, or with change in measles antibody status. There was a trend for children with lower baseline HIV-1 viral load to be more likely to be measles antibody positive at baseline and to seroconvert to measles antibody positive status after 6 months of HAART. Children converting from negative to positive for measles antibody had a baseline HIV-1 viral load that was approximately one-half log10 lower than children who remained antibody negative. It would therefore be difficult to identify children receiving HAART who would be more or less likely to require repeat immunization in the absence of antibody testing. Programs would need to re-vaccinate all children with immune reconstitution meeting CD4% criteria or measure measles antibody concentrations and only re-immunize those with low negative or borderline titers, as was done in this study, estimating that approximately 75% of these children would seroconvert to measles and tetanus antibody positive status following re-vaccination. Empiric re-vaccination may be more cost-effective and provide longer term benefits to programs. Notably, WHO policies do not include recommendations for either approach. This study provides further evidence for the need for such recommendations.
In conclusion, these data suggest that the WHO recommended vaccination schedules for HIV-1 infected children in developing countries may be inadequate. We found no significant increase in measles or tetanus responses post-HAART, and observed waning responses for 15 children who were initially tetanus antibody positive and later antibody negative and 10 children who were initially measles IgG positive. However, response to re-vaccination post-HAART was excellent. Additional boosters after immune reconstitution in regions where HAART is available appear to be necessary to achieve adequate immune responses. With increased access and use of HAART in pediatric populations, re-vaccination may have great benefit at the individual and community level for measles, tetanus and potentially other vaccine-preventable disease.