Humoral and cell-mediated immune responses to an early 2-dose measles vaccination regimen in the United States

BACKGROUND: Shifts in peak measles incidence to children <12 months old and the associated high mortality support the study of an early 2-dose measles vaccine regimen. METHODS: Fifty-five infants were vaccinated with measles vaccine at age 6 (n=32) or 9 (n=23) months, followed by measles-mumps-rubella (MMR)-II vaccine at age 12 months. A control group received MMR-II only at age 12 months. Measles-specific humoral and cell-mediated immunity were evaluated before, 12 weeks after measles immunization, and 24 weeks after MMR-II. RESULTS: Measles-specific T cell proliferation after both doses of vaccine was equivalent, regardless of age or the presence of passive antibodies. Seroconversion rates, geometric mean titers, and the percentage of infants with antibody titers >120 mIU after the first measles vaccine were lower in infants vaccinated at age 6 months, regardless of the presence of passive antibodies, but measles humoral responses increased after the administration of MMR-II vaccine in children initially vaccinated at age 6 or 9 months. CONCLUSION: Measles vaccination elicits T cell responses in infants as young as 6 months old, which may prime the humoral response to the second dose. Initiating measles vaccination as an early 2-dose regimen results in an immunologic response that is likely to have clinical benefits in developed and developing countries.     

Measles vaccination before nine months

Summary objective  To measure the protective effect of measles vaccine administered before 9 months of age and compare overall mortality of children vaccinated at 6–8 months and at 9–11 months.nsp;Non-concurrent cohort study involving all 13 134 children born between 16 January 1986 and 31st December 1991 in Kaniyambadi block near Vellore who had not left the area by six months of age. Main outcome measures were risk of disease and death among the under-five-year-olds according to age at measles immunization.ensp;Unimmunized children had a higher risk of developing measles compared to the immunized( P < 0.05). There was no significant difference in risk of measles among those vaccinated prior to and after nine months of age. Unvaccinated children were at significantly higher risk of death than vaccinated children ( P < 0.001). There was no difference in risk of death between infants vaccinated between 6 and 8 months and those vaccinated between 9 and 11 months. There was no difference in the risk of death between boys and girls vaccinated between 6 and 8 months with standard-titre Edmonston-Zagreb vaccine.p; Administration of standard-titre Edmonston-Zagreb measles vaccine at 6–8 months is an effective and safe preventive measure for measles, especially where the age-specific attack rate for childrenis high.     

Immunogenicity of standard dose Edmonston-Zagreb measles vaccine in highland Papua New Guinean children from four months of age

A small-scale trial was carried out at Tari in the Southern Highlands Province of Papua New Guinea to determine the effectiveness of a standard subcutaneous dose of Edmonston-Zagreb measles vaccine (Institute of Immunology, Zagreb) administered to children at less than 8 months of age. Specific antibody levels were measured before and 7-11 weeks after vaccination using an ELISA system. Paired sera from 41 children vaccinated at 4-7 months of age and from 18 children vaccinated routinely at 8-29 months of age were available for comparison. No child 6 months of age or older had detectable maternal antibodies and all of these seroconverted. Post-vaccination titres in 12 children aged 6-7 months were not significantly different from those in older children and 1 year later, post-vaccination titres were still high. In Papua New Guinea, and perhaps in other developing countries, it may prove appropriate and acceptable to vaccinate with Edmonston-Zagreb measles vaccine at 6 months of age without recourse to augmentation of dose from that currently recommended in older children.     

Field trial of a heat-stable measles vaccine in Papua New Guinea

In Papua New Guinea, consideration has been given to the introduction of measles vaccination, and a trial was conducted to determine the optimum age for vaccination and the suitability of a heat-stable measles vaccine (Rimevax) for countrywide use. As much of the vaccination programme is carried out by MCH teams on foot patrols, the trial was designed to determine immunogenicity of the vaccine after being transported and used for a week in a standard issue vaccine Esky by MCH staff. A study of the relevant literature having indicated 9 months as the probable best minimum age for measles vaccination, younger children were not included. The study was carried out on 313 infants and children aged nine to 24 months. An overall seroconversion rate of 96.6% was achieved using initially potent vaccine kept under field conditions for up to 102h. Ninety-seven percent of the vaccinees less than 11 months and 15 days of age seroconverted, as did all 15 children who were less than 70% of the Harvard standard weight for age. All 35 children who had seroconverted and who were retested six months after vaccination had detectable measles antibodies in their serum. Parental recollection of past measles infection was found unreliable as was reporting of post-vaccination reactions by parental recall since the incidence of reported 'reactions' in initially seronegative and seropositive vaccinees were similar. It is concluded that use of this heat-stable vaccine is possible with existing cold chain facilities in PNG and that infants can be vaccinated from the age of 9 months.     

The influence of HIV-1 exposure and infection on levels of passively acquired antibodies to measles virus in Zambian infants.

BACKGROUND: The age at which passively acquired antibodies are lost is critical to determining the optimal age for measles vaccination. Little is known about the influence of human immunodeficiency virus type 1 (HIV-1) infection on levels of prevaccination antibodies to measles virus. METHODS: Antibodies to measles virus were measured by plaque reduction neutralization assay in HIV-1-infected, HIV-seropositive but uninfected, and HIV-seronegative Zambian infants aged 6 weeks to 9 months. Regression models were used to estimate age-specific antibody concentrations. RESULTS: Neutralizing antibodies to measles virus were measured in 652 plasma samples collected from 448 infants, of whom 61 (13.6%) were HIV-1 infected, 239 (53.4%) were HIV seropositive but uninfected, and 148 (33%) were HIV seronegative. The best fitting model suggests that HIV-1-infected infants have lower levels of passively acquired antibodies to measles virus at birth than do HIV-seronegative infants, but their antibody levels decrease more slowly. By 6 months of age, 91% (95% confidence interval, 83%-99%) of HIV-1-infected infants, 83% (95% confidence interval, 77%-89%) of HIV-seropositive but uninfected infants, and 58% (95% confidence interval, 51%-64%) of HIV-seronegative infants were estimated to have antibody levels that were unlikely to affect immune responses to measles vaccine (cutoff value for immune response, <50 mIU/mL). By 9 months of age, 99% of all infants had antibody levels <50 mIU/mL. CONCLUSIONS: Infants born to HIV-1-infected women are less likely to have passively acquired antibodies that would neutralize measles vaccine virus and, thus, have an increased risk of measles prior to the age of routine vaccination. Protection could be achieved by administration of the first dose of measles vaccine prior to 9 months of age.     

Immune response to measles vaccine in 6 month old infants in Papua New Guinea

Objective  To assess the efficacy of the current measles immunization schedule in Papua New Guinea, which is to give the first dose at 6 months of age and the second at 9 months.
Methods  Humoral immune response study of 140 Papua New Guinean infants at 6 months of age, measuring measles IgG antibodies by enzyme immunoassay before and 85 days after the 6-month dose of measles vaccine.
Results  After vaccination at 6 months, 35.7% of infants developed a level of measles antibodies consistent with protection (IgG >330 IU/ml); 17.7% had an antibody response (150–330 IU/ml) that is likely to afford some protection; 46.8% had no detectable antibody response (IgG <150 IU/ml). Among 53 infants with no antibody response, 37 (69.5%) developed an antibody response, while 42.4% (37/87) of those with maternal antibodies sero-converted ( P  = 0.002).
Conclusions  Antibody response to measles vaccine was lower than expected at 6 months. While the presence of maternally derived antibodies accounted for some of the limited seroconversion in young infants, other factors are involved. Issues to be considered in determining the value of the first dose of measles vaccination in mid infancy in poor countries are complex and antibody responses are only one factor. Others, such as cell mediated immune responses, the non-specific protective effect of measles vaccine in preventing illness and death and the practicalities of uptake of vaccines at different ages, are also important.     

High effectiveness of aerosolized chick embryo fibroblast measles vaccine in seven-month-old and older infants

Neither the presence of hypertonic sugar nor the absence of 1% human albumin in the aerosolized chick embryo fibroblast (CEF) measles vaccine was previously found to be responsible for its inadequacy in infants with titers of maternal plaque-neutralizing (PN) antibody at which human diploid cell measles vaccine was immunogenic. Eight weeks after administration of CEF measles vaccine containing 1% human albumin, antibody had developed in all 10 infants 7-10 months old and all 11 children 12-35 months old but in only 26% of 23 infants 3-5 months old and 67% of 9 infants 6 months of age. Failure of antibody development was associated with prevaccination PN antibody titers of greater than or equal to 1:50 (with one exception at a titer of 1:25). The PN antibody response to CEF vaccine (diluted 1:10, approximately 10(5) pfu/ml) in infants under seven months of age (geometric mean titer [GMT], 1:421) was significantly lower (P less than .005) than in older infants (GMT, 1:1,564). At a 1:1,000 dilution of vaccine, only 50% of 10 infants 13-25 months old, 20% of 15 infants 7-10 months old, and none of 8 infants 6 months old developed antibody.     

Measles incidence, vaccine efficacy, and mortality in two urban African areas with high vaccination coverage

Measles incidence, vaccine efficacy, and mortality were examined prospectively in two districts in Bissau where vaccine coverage for children aged 12-23 months was 81% (Bandim 1) and 61% (Bandim 2). There was little difference in cumulative measles incidence before 9 months of age (6.1% and 7.6%, respectively). Between 9 months and 2 years of age, however, 6.1% contracted measles in Bandim 1 and 13.7% in Bandim 2. Even adjusting for vaccination status, incidence was significantly higher in Bandim 2 (relative risk 1.6, P = .04). Even though 95% of the children had measles antibodies after vaccination, vaccine efficacy was not more than 68% (95% confidence interval [CI] 39%-84%) and was unrelated to age at vaccination. Unvaccinated children had a mortality hazard ratio of 3.0 compared with vaccinated children (P = .002), indicating a protective efficacy against death of 66% (CI 32%-83%) of measles vaccination. These data suggest that it will be necessary to vaccinate before age 9 months to control measles in hyperendemic urban African areas.     

Association between measles antibodies in vaccinated and naturally infected mothers with protective antibodies and the occurrence of measles in their children:A cross-sectional study in the Bavi district of Hanoi

Objective:To determine the concentration and rate of decay of maternal IgG antibodies against measles prevalence in infants of vaccinated or naturally infected mothers and study initial measles immunization occurs in nine-month-old children.Methods:In total,401 pregnant women and the same number of their subsequent newborns were recruited in the Bavi district of Hanoi in 2016-2017;they were divided into two groups:Older women(born before 1985,n=201)and younger women(born after 1990,n=200).Samples were collected at five time-points;week 36 of pregnancy,birth(cord),and 3,6,and 9 months after birth.Measles-specific IgG antibody levels were recorded.Results:In total,77.06% of the 401 pregnant women were seropositive for measles-specific IgG antibodies.A significantly greater proportion of mothers aged 30 and older(88.06%)and their newborn(93.53%)were seropositive compared to the mothers aged 25 and younger(66.00%),and their newborn(72.00%)(P0.001).The infants of older mothers had significantly higher geometric mean titres(GMT)of measles IgG antibodies than the infants of younger mothers(P0.001)at all time-points of the study period.The proportion of measles IgG antibodies together with GMT decreased from 82.97%(506.96)at the age of three months to 23.19%(45.22)at the age of nine months.Conclusions:This study provides a profile of maternal antibodies against measles in Vietnamese infants and investigates the early susceptibility to measles in both the infants of vaccinated mothers and mothers with naturally acquired immunity.These data suggest that determining the appropriate age for measles vaccination is paramount for the elimination of measles in Vietnam.     

Field trial of combined measles and rubella live attenuated vaccine

We investigated the antibody responses and clinical adverse reactions after immunization with live combined measles and rubella vaccine (HF vaccine) in 442 healthy children, aged 12-90 months of age. We obtained 368 paired sera. Among them, 363 were initially sero-negative against measles virus and 343 (94.5%) became sero-positive after immunization. Sero-conversion against rubella virus was demonstrated in 349 (96.7%) of 361 initially sero-negatives against rubella virus. We investigated the clinical adverse reactions in 406 recipients. In 102 (25.1%) recipients, febrile reaction (> 37.5 C) developed on the day 6.7 of vaccination on average, with a mean duration of 2.2 days. Only two (0.5%) developed high body temperature over 39.5 C. Skin rash was noted in 87 (21.4%) on day 7.1 of vaccination on average, with a mean duration of 4.8 days. Lymphoadenopathy was demonstrated in 12 (3.0%). Thus, measles and rubella combined vaccine was safe and sufficiently immunogenic as well as each monovalent one, having clinical advantage in immunization practice.     

Immunogenicity of measles and rubella vaccines in Oman: a prospective clinical trial

A prospective immunogenicity trial of measles and rubella vaccines was conducted in Oman. Children received measles vaccine at age 9 months and measles-rubella vaccine at age 15 months. Serum specimens were tested for measles-specific IgG and rubella-specific IgG. Of 1025 eligible infants, 881 (86.0%) returned for all five visits and had adequate serum samples for testing. Seroconversion to measles after vaccination at 9 months was 98.1%. At 15 months, 47 (5.3%) of the 881 children were seronegative for measles; of these, 44 (93.6%) seroconverted. At 16 months, 99% of the children seronegative at age 9 months seroconverted after receiving two doses of measles vaccine. At age 15 months, 684 (77.6%) children were seronegative for rubella. Of these, 676 (98.8%) seroconverted by age 16 months. One dose of measles vaccine at age 9 months was highly immunogenic. One dose of measles-rubella vaccine at age 15 months closed the remaining measles immunogenicity gap and resulted in a high rate of rubella seroconversion.     

Induction of cellular and humoral immunity after aerosol or subcutaneous administration of Edmonston-Zagreb measles vaccine as a primary dose to 12-month-old children

Infants were immunized by aerosol (10(3.6) plaque-forming units [pfu]/dose) or subcutaneous (sc) (10(4.27) pfu/dose) administration of Edmonston-Zagreb measles vaccine. Measles-specific T cell proliferative responses with a stimulation index of > or =3 developed in 72% of children given aerosol-administered vaccine, compared with 87% given s.c.-administered vaccine (P =.06). Seroconversion rates were 90% after aerosol-administered vaccine and 100% after s.c.-administered vaccine (P=.01), and measles geometric mean titers were 237 milli-international units (mIU) (95% confidence interval [CI], 146-385 mIU) and 487 mIU (95% CI, 390-609 mIU) in each group, respectively (P=.01). Measles-specific T and B cell responses were weaker after aerosol than after sc vaccination, indicating a need to use a higher aerosol dose to achieve optimal immunogenicity.     

A serosurvey to identify the window of vulnerability to wild-type measles among infants in rural Mali

As infants lose maternally derived antibody, they experience a period when antibody levels are insufficient to protect against measles yet may interfere with immunization. In Kangaba Mali, sera were collected from 89 2-8-month-old infants and 32 9-10-month-old infants without a history of measles or vaccination; post-vaccination sera were collected from 24 of the 9-10-month-old infants 3-5 weeks after receiving measles vaccine. Measles antibody was measured by plaque reduction neutralization (PRN) and enzyme linked immunosorbent assay. At two months of age, 30% had protective PRN titers; among six-month-old infants, none had protective titers. Prior to vaccination, 16% of 9-10-month-old infants exhibited protective titers; all demonstrated protective titers post-vaccination. The early onset of the window of vulnerability in Kangaba infants likely reflects the changing ecology of measles in Africa. Ways to protect these vulnerable infants against measles must be devised.     

Age-dependent differences in IgG isotype and avidity induced by measles vaccine received during the first year of life

BACKGROUND: Measles remains an important cause of death worldwide, and vaccinating individuals at an earlier age could lead to better control of the disease. However, persistence of maternal antibody and young age affect the quantity of vaccine-induced neutralizing antibody and may also affect antibody quality. METHODS: Enzyme immunoassay was used to analyze measles virus-specific IgG levels, avidity maturation, and isotype changes, using serum samples from infants who received measles vaccine at 6 months of age and measles-mumps-rubella (MMR)-II at 12 months of age (n=26), measles vaccine at 9 months of age and measles-mumps-rubella (MMR)-II at 12 months of age (n=48), or only MMR-II at 12 months of age (n=27). RESULTS: The median IgG level was lower among infants with maternal antibody than among those without maternal antibody. Compared with median avidity indices for infants aged 12 months, median values were lower for 6-month-old infants with maternal antibody (P=.0001), 6-month-old infants without maternal antibody (P=.001), 9-month-old infants with maternal antibody (P=.03), and 9-month-old infants without maternal antibody (P=.006). The median IgG3 level was highest at 6 months of age. IgG1 was predominant at 12 months. Low avidity responses at 6 or 9 months of age did not hinder higher avidity responses or the switch to IgG1 after secondary vaccination. The 2-dose regimen did not augment the response, compared with the response in infants who received 1 dose at 12 months of age. CONCLUSIONS: Avidity and isotype maturation of measles vaccine-induced antibody are affected by age, providing insight into the ontogeny of the immune response to measles vaccine.     

Measles immunization in Iran

Mass immunization with live measles vaccine has been carried out in rural Iran since 1968. Two strains have been used: primary baby calf kidney cell-adapted Sugiyama strain and human diploid cell-adapted AIK strain. More than 94% of the susceptible children experimentally vaccinated with either of the two vaccines have shown seroconversion. Mass immunization in rural regions has covered about 80% of susceptible children. It is now recommended that the live vaccine be administered twice: the first dose at six to nine months and the second at 12-15 months of age. In all of 100 cases of subacute sclerosing panencephalitis (SSPE) observed in the Tehran region between 1977 and 1982, the patient had a history of measles infection in childhood; there was no indication that SSPE developed after vaccination. Most of the patients with SSPE have had a high titer of antibody to measles virus in serum and cerebrospinal fluid, and antibody has commonly been demonstrated in saliva as well.     

Immune responses to measles immunization and the impacts on HIV-infected children.

This prospective cohort study was conducted to determine the seroconversion rate and the pattern of antibody response to measles vaccine administered at age 9 months in HIV infected and non-infected children born to HIV-1 seropositive mothers. Thirty children born to HIV-1 seropositive mothers and 3 born to HIV-1 seronegative mothers were recruited. One single dose of Schwarz strain of measles virus vaccine (Rouvax) was given to every child at 9 months of age. Clinical status and measles antibody levels were evaluated at the time just before vaccination, 2 and 12 weeks post-vaccination. Antibody was measured by an enzyme immunoassay commercial kit (Enzygnost, Dade Behring Manufacturer, Germany). Children were classified into 3 groups, groups 1 and 2 were children with and without HIV infection respectively. Group 3 children were those born to HIV-1 seronegative mothers. Of the 33 enrolled children, 16, 14 and 3 were classified as groups 1, 2 and 3 respectively. Four children, 2 of each, in groups 1 and 3 did not complete the study. Group 3 was excluded due to the small number of children recruited. There was no short term complication and no measles infection noted during the course of study. None of the children had pre-existing antibodies. The median (range) of CD4 count and CD4/CD8 ratio measured at the time of vaccination were statistically different between groups 1 and 2 children. Group 2 children had better antibody response than group 1 in terms of seroconversion rate and median of antibody levels at 12 weeks post-vaccination. Only 7 of 29 children (24.1%) had detectable measles antibodies at 2 weeks post-vaccination. A decrease in antibody was noted in 2 symptomatic HIV infected children as their disease had progressed. Various potential predictors of measles vaccine responses in HIV infected children including CD4 count and CD4/CD8 ratio were not statistically different between the responders and non-responders. All 4 asymptomatic HIV infected children were responders. This study demonstrated that all of the children had already lost their maternal acquired antibodies at age 9 months. HIV infected children had a poorerantibody response to measles vaccine than the non-infected children.     

Prospective trial of timing of bacillus Calmette-Guérin vaccination in Canadian Cree infants

We studied 184 Cree Indian infants in randomized, prospective fashion to assess the effect of age on lymphocyte sensitization to purified protein derivative (PPD) before and after and without bacillus Calmette-Guérin (BCG) vaccination. Lymphocyte responses to PPD, Candida, and streptokinase were measured at birth and at intervals later. The mean response of paired values from 26 infants without BCG vaccination rose for the PPD stimulation index (SI) from 2.7 at birth to 3.9 before 2 yr of age. The SI for both Candida and streptokinase for this group of infants rose significantly in the first 2 yr (p less than 0.05). In 66 infants who received BCG in the first 7 days of life, the PPD-SI rose from 3.1 to 35.3 (p less than 0.001). In 17 infants who received the vaccine later but before 9 months, it rose from 3.1 at birth to 24.9, and in 14 who received it between 9 months and 2 yr, it rose from 2.2 to 52.9. The lymphocyte responses to PPD after BCG in these two groups were significantly different (p less than 0.05). There was no evidence in the older infants that a raised PPD-SI before BCG vaccination affected lymphocyte sensitization by the vaccine. We conclude that increasing the age at vaccination with BCG from birth to more than 9 months enhances immunologic sensitization to PPD significantly in this population.     

Aseptic meningitis in a large MMR vaccine campaign (590,609 people) in Curitiba, Paraná, Brazil, 1998.

The aseptic meningitis after Measles-Mumps-Rubella vaccine (MMR) is a well recognized complication, and different incidences have been observed in several studies. We retrospectively analyzed forty cases of aseptic meningitis, during a large public immunization campaign (1998) in Curitiba, Southern Brazil (590,609 people), admitted in our Service. The vaccine utilized was Leningrad-3-Zagreb mumps strain, Edmonston-Zagreb measles strain, and RA 27#3 rubella strain. In all county, a total number of 87 cases were reported, resulting in a incidence of 1.7 cases per 10,000 given doses. The mean age was 23.7 +/- 12.8 years. The female:male ratio was 1.35:1. Severe headache with meningismus (92.5%), fever (87.5%), nausea/vomiting (82.5%) were the most common clinical findings. Three cases (7.5%) developed mild mumps. All patients underwent cerebrospinal fluid (CSF) tap with the following findings: mononuclear pleocytosis from 100 to 500 cells/mm(3) in 17 cases (42.5%; 257.5 +/- 260.6 cells/mm3); increased protein 28 cases (67.5%; 92.1 +/- 76.9 mg/dL); glucose was normal in all cases (56.8 +/- 11.2 mg/dL) except in 4 (10%) cases, which presented less than 44 mg/dL. All serological tests (latex to bacterial meningitis, Cryptococcus, cysticercosis, VDRL) and bacteriological cultures were negative. Virus identification were also negative in 8 samples. None of the patients had neurological deficits or related symptoms after one year of onset. We believe the benefit of vaccination clearly outweighs the incidence of benign vaccine-associated meningitis.     

Immunization of healthy children with mumps-rubella bivalent live vaccine and simultaneous vaccination with mumps-rubella and varicella vaccines]

Bivalent virus vaccine, containing rubella TCRB-19 strain and mumps NK-M46 strain (MR vaccine), was administered to a total of 95 healthy children who had already received measles vaccine or had been infected with wild measles virus. The seroconversion rates for rubella and mumps viruses in subjects having no antibody to rubella or to mumps virus were 99% (75/76) and 97% (63/65), respectively, at 6-8 weeks after vaccination. The seroconversion rates for both rubella and mumps in vaccinees initially seronegative to both viruses were 95% (56/59). Immune responses after MR vaccine injection were comparable to those after administration of monovalent rubella or mumps vaccine. Clinical reactions observed in some subjects who received MR vaccine were mild fever (3.6%), exanthem (8%), lymphadenopathy (1.8%), and swelling of the parotis region (1.8%). MR vaccine could be simultaneously injected with varicella vaccine at the opposite site producing no adverse effect on immune response. Our results indicate that MR vaccine is a safe and effective vaccine, especially for children who have had wild measles or who have received measles vaccine.     

Increased risk of early measles in infants of human immunodeficiency virus type 1-seropositive mothers.

An increase in illness due to measles is one of the potential consequences of the human immunodeficiency virus (HIV) epidemic in Africa. During a study of perinatal HIV transmission conducted in Kenya, the risk of acquiring measles before vaccination (9 months of age) was found to be 3.8 times higher in infants born to HIV-seropositive mothers than in control infants (10 [9%] of 109 vs. 5 [3%] of 194 infants; P = .02; odds ratio, 3.8; 95% confidence interval, 1.2-13.2). The majority of infants who developed measles in this study had significant sequelae related to their measles infection. The increased risk of measles appeared to be related to relatively lower anti-measles antibody titers detected in cord blood samples of affected infants born to HIV-seropositive mothers. However, 94% of all infants were susceptible to measles on the basis of ELISA testing at age 6 months regardless of maternal HIV serology. These observations highlight the need for improved measles vaccination strategies in Africa and for studies to delineate the effects of HIV infection on the incidence, presentation, and sequelae of childhood infectious illnesses.