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Measles control efforts in urban Africa complicated by high incidence of measles in the first year of life.

A measles vaccination coverage of between 50 and 60% has been achieved in Kinshasa, Zaire, from 1980-1985. During that interval, the annual number of measles cases and the incidence rate of measles reported by a surveillance system remained similar, and measles epidemics occurred in alternating years. The estimated number of measles cases in Kinshasa is 87,600 per year. Of reported measles cases, 27% occurred in children under nine months of age, younger than the recommended age at vaccination. Two results expected in a partially vaccinated population, a reduction in measles incidence greater than the level of vaccination coverage and a shift in the age distribution of measles to older children, have not been observed. Measles control in Kinshasa will require a vaccination coverage of higher than 60%. In addition, given the age-specific risk of measles infection here, a measles vaccine that would be effective when given before nine months of age would be an important element in controlling measles transmission. Because the epidemiology of measles in Kinshasa is a likely consequence of its urban environment, such a vaccine would represent a significant advance toward the control of measles in urban Africa.

Age Factors↗

Comparative analysis of host responses related to immunosuppression between measles patients and vaccine recipients with live attenuated measles vaccines.

Measles virus infection induces a profound immunosuppression. We analyzed in a time-dependent manner peripheral bloods of one to two-year-old children immunized with live attenuated measles vaccines, compared with age-matched measles patients, for immunosuppression. In contrast to transient severe lymphopenia with measles patients, primarily due to extensive apoptosis of a broad spectrum of uninfected lymphocytes, neither apoptosis nor lymphopenia occurred with measles vaccine recipients. Increase in number and activation of NK cells, which might compensate for the lymphopenia in measles patients, were not found with the vaccinees. While cell surface expression of apoptosis-related molecules such as TNF-related apoptosis-inducing ligand (TRAIL), TRAIL-receptors, CD95(Fas) and Fas-ligand, and plasma interferon-gamma were increased for measles patients, they remained unchanged after vaccination. Plasma interleukin (IL)-18, which is responsible for inducing apoptosis in several infectious diseases, was increased predominantly with measles patients, whereas the increase remained marginal with the vaccinees. IL-10 was elevated transiently in both measles patients and vaccinees. Decrease in plasma IL-12, which is often correlated with T cell suppression, was not found for both cases. Serum IgM and IgG antibodies to measles virus were induced at lower titers in the vaccinees than measles patients. These results indicate that in contrast to wild-type measles virus, live measles vaccines hardly provoked host cytokine responses that lead to apoptotic cytolysis of uninfected lymphocytes, lymphopenia and immunosuppression, and thereby induced weaker immune responses to the virus.

Antibodies, Viral↗

Evaluation of recombinant vaccinia virus--measles vaccines in infant rhesus macaques with preexisting measles antibody.

Immunization of newborn infants with standard measles vaccines is not effective because of the presence of maternal antibody. In this study, newborn rhesus macaques were immunized with recombinant vaccinia viruses expressing measles virus hemagglutinin (H) and fusion (F) proteins, using the replication-competent WR strain of vaccinia virus or the replication-defective MVA strain. The infants were boosted at 2 months and then challenged intranasally with measles virus at 5 months of age. Some of the newborn monkeys received measles immune globulin (MIG) prior to the first immunization, and these infants were compared to additional infants that had maternal measles-neutralizing antibody. In the absence of measles antibody, vaccination with either vector induced neutralizing antibody, cytotoxic T cell (CTL) responses to measles virus and protection from systemic measles infection and skin rash. The infants vaccinated with the MVA vector developed lower measles-neutralizing antibody titers than those vaccinated with the WR vector, and they sustained a transient measles viremia upon challenge. Either maternal antibody or passively transferred MIG blocked the humoral response to vaccination with both WR and MVA, and the frequency of positive CTL responses was reduced. Despite this inhibition of vaccine-induced immunity, there was a reduction in peak viral loads and skin rash after measles virus challenge in many of the infants with preexisting measles antibody. Therefore, vaccination using recombinant vectors such as poxviruses may be able to prevent the severe disease that often accompanies measles in infants.

Animals↗

The effect of human immunodeficiency virus-1 infection and stunting on measles immunoglobulin-G levels in children vaccinated against measles in Uganda.

BACKGROUND: Measles is an important public health problem in developing nations and there is concern that immune response to measles vaccination may be compromised by paediatric human immunodeficiency virus (HIV) infection. Therefore, this study investigated the relationship of immunoglobulin-G (Ig-G) antibody levels in children vaccinated against measles and HIV-1 infection. Further analysis was done to assess the influence of nutritional status on this relationship. METHODS: The authors measured HIV and measles antibodies in 243 vaccinated children aged 17-41 months from Kampala, Uganda. Children were from paediatric and HIV clinics. Potential confounders of this relationship included nutritional anthropometric measures, age at and time since vaccination, measles exposure, family crowding, vaccination clinic and gender. Univariable and multivariable analyses were used to study these associations. RESULTS: Fifty children (21%) were HIV infected. In univariable analysis, low measles antibody (<15 ELISA units/ml) was associated with HIV (P = 0.05; odds ratio (OR) = 1.86) and stunting (P = 0.06; OR = 1.68). Stunting, measured as height-for-age and defined as <-2 standard deviations of the reference population median, was a surrogate for chronic malnutrition. HIV was strongly associated with stunting (P = 0.0001; OR = 6.62). In multiple logistic regression, HIV was not associated with low measles antibodies; however, stunting (P = 0.04; OR = 1.81), and <3 children in the home (P = 0.01; OR = 1.96) were. Conversely, being male (P = 0.05; OR = 0.58), and measles in the home in the previous month (P = 0.04; OR = 0.33) were associated with high antibody levels. CONCLUSIONS: These findings suggest that HIV in Ugandan children immunized for measles may indirectly interfere with measles antibody levels by causing malnutrition, the latter being the direct cause. Programmes to improve childhood nutrition, especially for HIV-infected children, should accompany measles control programmes in developing nations for maximum benefit from measles vaccination. HIV infection per se should not change measles vaccination programmes.

Analysis of Variance↗

Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study.

BACKGROUND: Previous studies have suggested that standard measles vaccine may reduce mortality by more than the number of deaths thought to be caused by measles infection in areas with high mortality. However, these observations have not been based on randomized trials. METHODS: During the recent war in Guinea-Bissau, most children fled from the city of Bissau and immunization services in the country broke down for several months. We were performing a trial in which children were randomized at 6 months of age to receive either measles vaccine or inactivated polio vaccine. Because of the war many children did not receive the dose of measles vaccine planned for 9 months of age. We were able to monitor mortality during the war and after. RESULTS: Included in the study were 433 children 6 to 11 months of age. Fifteen children died (3.6%) during the first 3 months of the war before vaccination programs were resumed, 4 of 214 measles-vaccinated children and 11 of 219 children who had received inactivated polio vaccine. The effect of measles vaccine was marked for girls [mortality rate ratio (MR), 0.00; 95% confidence limits, 0.0 to 0.37], whereas there was no difference for boys (MR = 1.02; 95% confidence limits, 0.25 to 3.88). In a combined analysis controlling for factors that differed between the two groups, the MR for measles-vaccinated children was 0.30 (95% confidence limits, 0.08 to 0.87). Prolonging the period of observation to the end of 1998 or including the prewar period did not modify the significant beneficial effect of measles vaccine for girls. Twenty-two of the children in the cohort were reported to have had measles, 8 cases occurring during the 3 months of the war. Exclusion of measles cases in the analysis did not change the results; children who had received measles vaccine had a MR of 0.28 (95% confidence limits, 0.06 to 0.89) during the first 3 months of the war. CONCLUSIONS: Consistent with previous observational studies, measles vaccination was associated with a reduction in mortality that cannot be explained by the prevention of measles infection. This nonspecific beneficial effect was particularly strong for girls. Further studies are needed to examine the extent of nonspecific effects in settings with high mortality.

Cause of Death↗

Decline of measles-specific immunoglobulin M antibodies after primary measles, mumps, and rubella vaccination.

Detection of measles-specific immunoglobulin M (IgM) has become the standard diagnostic method for laboratory confirmation of measles. In outbreaks, the interpretation of an IgM-positive result can be complicated when persons with suspected measles receive a dose of measles vaccine as part of outbreak control measures. This investigation evaluated the decay of measles-specific IgM antibodies 1 to 4 months after primary vaccination with measles, mumps, and rubella vaccine (MMRII). Serum samples were obtained from 536 infants vaccinated when they were 15 months old as part of a study to assess primary and secondary measles vaccine failure. Sixty serum specimens per week were selected from specimens collected between 4 and 9 weeks after MMRII vaccination; all 176 available serum specimens collected between 10 and > or = 16 weeks were included. Specimens were tested for the presence of measles-specific IgM by an antibody-capture enzyme immunoassay. The proportion of IgM-positive specimens dropped from 73% at 4 weeks after vaccination to 52% at 5 weeks after vaccination and then declined to 7% by 8 weeks after vaccination. Less than 10% of children remained IgM positive between 9 and 11 weeks. An IgM-negative result helps rule out the diagnosis of measles in a person with suspected infection and a history of recent vaccination. The interpretation of a positive IgM result from a person with a clinically suspected case of measles and a recent history of measles vaccination (especially within 8 weeks) is problematic, and the diagnosis of measles should be based on epidemiologic linkage to a confirmed case or on detection of wild-type measles virus.

Antibodies, Viral↗

Epidemiologic studies of measles, measles vaccine, and subacute sclerosing panencephalitis.

Histories obtained in 350 of 375 clinically cofirmed cases of subacute sclerosing panencephalitis (SSPE) reported to a national registry showed that 292 patients had measles and 58 had no history of measles. Forty of the latter patients received live, attenuated measles virus vaccine. In patients with a history of measles, measles illness occurred before age 2 years in 46%, and a mean of 7.0 years before onset of SSPE. In contrast, there was no relationship of SSPE with age at vaccination in 35 of the 40 patients historically associated with measles vaccine, and SSPE occurred a mean of 3.3 years after vaccination. Based on estimated national measles morbidity data and national measles vaccine distribution data, the risk of SSPE following measles vaccination (0.5 to 1.1 cases/106) appears to be less than the risk following measles (5.2 to 9.7 cases/106). Because live measles vaccine is highly effective in preventing measles illness and a high proportion of children in the United States have received measles vaccine, these data are consistent with the observed downward trend in SSPE incidence since 1969.

Adolescent↗

A survey of hospital infection control policies and employee measles cases during Los Angeles County's measles epidemic, 1987 to 1989.

BACKGROUND: Between December 1987 and December 1989, 74 adults employed in Los Angeles County acute care hospitals were found to have measles. To investigate measles infection control policies in Los Angeles County and to gain information on employee measles cases, two surveys were performed. METHODS: A survey of all infection control practitioners (N = 102) of acute care hospitals was conducted in July 1989. Reported employee measles cases were surveyed after initial case reports were reviewed. RESULTS: The survey of acute care hospitals revealed that only 17% had mandatory measles infection control policies requiring written proof of past measles vaccination, disease, or seropositivity. Only 4% of hospitals had policies affecting students or volunteers. A second survey of hospital employees with confirmed measles revealed that 46% (34/74) were working in hospitals without measles infection control policies, 43% (32/74) were born before 1957, and 31% (21/67) were working in jobs not traditionally considered to provide a high risk of measles exposure. One third of the sick employees were hospitalized. The standard of either birth date before 1957 or oral history of measles illness or vaccination would have classified 93% (39/42) of the employees with measles as immune. CONCLUSIONS: Effective infection control policies against measles and rubella should be adopted and enforced. Those policies should only allow written documentation as proof of measles immunity and should address all employees, regardless of age or job description.

Adult↗

T cell immunity to measles viral proteins in infants and adults after measles immunization.

Vaccination of infants against measles remains of global importance, and proposed new vaccine strategies include the use of measles proteins or synthetic peptides as immunogens. We studied cell-mediated immunity to whole measles antigen and measles proteins in immune adults and infants after measles vaccine. Further, we measured CD8+ T cell responses to peptide pools corresponding to the nucelocapsid (N) measles protein in adults given measles vaccine. Cell-mediated immune responses to three of four measles proteins were equivalent to those against whole measles antigen in immune adults. Responses to the fusion (F) protein were lower in infants compared to whole measles antigen (p < or = 0.03). Infant responses to both whole measles antigen and the F protein were lower compared with these responses in adults (p < or = 0.001). CD8+ T cell responses to N peptide pools varied, and differed between immune HLA-A2-positive individuals compared with naive and HLA-A2-negative subjects after measles vaccination. The measles-specific T cell adaptive response of infants is limited compared to adults, including responses to the F protein.

Adult↗

Induction of measles virus-specific human cytotoxic T cells by purified measles virus nucleocapsid and hemagglutinin polypeptides.

The measles virus polypeptide specificity of human measles virus-specific, HLA class II restricted cytotoxic T cells have been examined. Measles virus-specific CTL have been generated using purified measles virus nucleocapsid and hemagglutinin polypeptides during a primary, in vitro stimulation of bulk cultures. Both the purified preparations of measles virus nucleocapsid and hemagglutinin polypeptides were effective in stimulating a measles virus-specific CTL response. The measles virus nucleocapsid-induced CTL response could be blocked by an anti-HLA class II monoclonal antibody but not an anti-HLA class I antiserum. Moreover, considerably less measles virus nucleocapsid was required to stimulate a comparable CTL response than the measles virus hemagglutinin which suggests that the CTL response to measles virus may be skewed towards internal viral determinants of measles virus. These studies indicate that both internal and external components of measles virus are effective in inducing measles virus-specific CTL. The recognition of internal viral components may represent an important part of the T cell mediated immune response to viruses.

Antibodies, Monoclonal↗

Western blot analyses of measles virus antibody in normal persons and in patients with multiple sclerosis, subacute sclerosing panencephalitis, or atypical measles.

A version of the Western blot was developed to detect serum antibodies against measles virus polypeptides. With this technique, a seroepidemiological survey of antibodies to the several measles virus proteins in diverse measles-related conditions was conducted. The sera were obtained from individuals with a recent or long-past history of natural measles, from persons with a history of immunization with live attenuated measles vaccine, and from patients with multiple sclerosis, subacute sclerosing panencephalitis, or atypical measles. The findings indicated that live attenuated measles vaccine elicits an antibody response qualitatively resembling that of a natural infection. In addition, multiple sclerosis patients made less antibody to the measles virus M protein than did individuals with a long-past history of natural measles. Thus, the immunological reaction of multiple sclerosis patients to measles virus is qualitatively, as well as quantitatively, different from that of normal persons. Finally, persons with subacute sclerosing panencephalitis and atypical measles mounted abnormally high antibody responses to measles virus polypeptides, in particular the P protein.

Adolescent↗

Measles IgA in the nasal washings of adult volunteers and children immunized intranasally with measles vaccine L-16.

Earlier it was determined that inspiration of aerosolized measles vaccines may be as effective as its injection in induction of measles antibodies formation. In the beginning of measles infection the measles virus penetrates through mucosa of nose, mouth or eyes of children. So it seems rational to use a nasal spray of measles vaccine to induce "mucosal immunity" in the nasopharinx. Local IgA measles antibodies formation was observed only after measles vaccine spray immunization of 6-7 year old children or adult volunteers. The same level of sera measles antibodies was observed in immunized people after intranasal or subcutaneous measles vaccination. Special investigation of measles vaccination side effects in adults revealed that the injected vaccine suppressed lymphocytes functional capacity much more than when intranasally introduced. Intranasal measles vaccine spray introduction may be a useful method of child revaccination in the process of measles eradication. This method is useful for investigation of "mucosal immunity" in children or adults.

Administration, Intranasal↗

Measles-specific lymphocyte reactivity and serum antibody in subjects with different measles histories.

Measles hemagglutination-inhibiting (HAI) antibody titers and measles-specific lymphocyte reactivity were studied in subjects who had previously received killed measles vaccine and had been recently reimmunized with live vaccine--persons who previously had atypical measles, subjects with multiple immunizations with live vaccine, adults with a history of measles, and persons with primary measles immunization. Twelve to 18 months after revaccination of former recipients of killed vaccine, all 31 subjects had measles HAI antibody titers greater than or equal to 10 and only three had lymphocyte stimulation indices (LSI) greater than 2.8. The mean LSI and geometric mean titer of antibody were similar to those of persons who had had natural measles many years ago. One subject who previously had atypical measles had an HAI titer of less than 5 and an LSI of 0.5; another had an LSI of 6.0 and an HAI titer of 80. Only one of seven subjects who were immunized more than once with live vaccine had an LSI of greater than 2.8 one year later. The finding of measles-specific lymphocyte reactivity and antibody levels in revaccinated former recipients of killed vaccine that are similar to those in persons who had natural measles suggests that the risk of future atypical measles in this group is slight.

Adolescent↗

Cocirculation of measles virus genotype B2 and B3.1 in Central African Republic during the 2000 measles epidemic.

Many African countries have begun implementation of national programs to eliminate measles by the year 2015. However, measles continues to be endemic in Africa. This study describes the first molecular epidemiological study of measles virus circulating in Central African Republic. Two hundred and ten blood samples were tested for measles IgM. Sixty-seven urine samples were collected during measles outbreak in Bangui in 2000 and 2004 and used for genotyping studies. Two different methods were used to determine measles virus genotypes; the recently described real-time PCR-based method and the nucleotide sequencing and phylogenetic analysis methods. These tests revealed the cocirculation of two distinct viruses in Bangui. The proposed subgroup of the B3 genotype, B3.1 was found in 14 samples. This virus has been found in other neighboring countries. More surprising, genotype B2 was found in samples from four patients. The first measles genotype B2 viruses were isolated in Gabon in 1984, but have not been detected until recently when they were identified during a measles outbreak in 2003 in South Africa. This suggests that the circulation of measles genotype B2 has continued in Central Africa during the last 20 years. This study provides the baseline for genetic surveillance of measles virus in Central African Republic. Knowledge of currently circulating measles virus genotype in Central African Republic will help in monitoring the success of measles elimination program.

Base Sequence↗

HLA class II alleles and measles virus-specific cytokine immune response following two doses of measles vaccine.

Measles virus-specific T cells and the production of cytokines play a critical role in the immune response following measles immunization. To understand the genetic factors that influence variation in IFN-gamma and IL-4 responses following measles immunization and to provide insight into the factors influencing both cellular and humoral immunity to measles, we assessed associations between human leukocyte antigen (HLA) class II genes and measles-specific Th1 and Th2-type cytokine responses in peripheral blood lymphocytes from 339 children previously vaccinated with two doses of measles-mumps-rubella vaccine (MMR-II). Median values for measles-specific IFN-gamma and IL-4 secretion levels were 40.73 and 9.71 pg/ml, respectively. The global tests suggested associations between measles-specific IFN-gamma response and alleles of the DRB1 and DQB1 loci (P=0.07 and P=0.02, respectively). Specifically, DRB1*0301, *0901, and *1501 alleles were significantly associated with IFN-gamma secretion. The alleles that suggested evidence of an HLA association with IL-4 secretion were DRB1*0103, *0701, and *1101. Th1 cytokine responses and DQB1 allele associations revealed that the alleles with the strongest association with IFN-gamma secretion were DQB1*0201, *0303, *0402, and *0602. Specific alleles with a suggestive association with low measles-specific Th2 cytokine responses were DQB1*0202 and *0503. In addition, DPB1*0101, *0201, and *0601 alleles provided suggestive evidence of an HLA association with measles-induced IFN-gamma response, while DPB1*0501 was associated with an IL-4 response. These data suggest that IFN-gamma and IL-4 cytokine responses to measles may be genetically restricted in part by HLA class II genes, which in turn can restrict the cellular immune response to measles vaccine.

Adolescent↗

Measles infection, measles vaccination and the effect of birth order in the aetiology of hay fever.

BACKGROUND: It has recently been suggested that measles infection may reduce the risk of atopy. OBJECTIVE: To study the independent effect of measles infection and measles vaccination on the occurrence of hay fever in a British national birth cohort. METHODS: In over 6000 children born in 1970, details of immunizations and childhood diseases were collected by parental interviews at ages 5, 10 and 16 years, and hay fever within the past year at age 16 years. RESULTS: In univariate analysis, hay fever was less common in those contracting measles infection than in those not infected (OR 0.86, 95% CI 0.76-0.96), and more common in those given measles vaccination than in those not vaccinated (OR 1.16, 95% Cl 1.03-1.31). However, these effects were strongly confounded by birth order, which was closely associated with the likelihood of receiving measles vaccination and with the risk of hay fever. A strong interaction between the effects of measles vaccination and infection, and birth order was found, such that in those with many older sibling contacts, hay fever was significantly and independently reduced in relation to both measles infection and measles vaccination relative to those who were neither infected nor vaccinated. CONCLUSIONS: Both measles infection and measles vaccination in childhood appear to reduce the risk of hay fever in children with multiple older sibling contacts. Differential exposure or response to the measles virus may explain the effect of birth order on the occurrence of allergic disease.

Adult↗