Immunological impact of an additional early measles vaccine in Gambian children: responses to a boost at 3 years

Background

Measles vaccine in early infancy followed by a dose at 9 months of age protects against measles and enhances child survival through non-specific effects. Little is known of immune responses in the short or long term after booster doses.

Methods

Infants were randomized to receive measles vaccine at 9 months of age (group 1) or 4 and 9 months of age (group 2). Both groups received a boost at 36 months of age. T-cell effector and memory responses using IFN-γ ELIspot and cytokine assays and antibody titres using a haemagglutination-inhibition assay were compared at various times.

Results

Vaccination at 4 months of age elicited antibody and CD4 T-cell mediated immune responses .Two weeks after vaccination at 9 months of age group 2 had much higher antibody titres than group1 infants; cell-mediated effector responses were similar. At 36 months of age group 2 antibody titres exceeded protective levels but were 4-fold lower than group 1; effector and cytokine responses were similar. Re-vaccination resulted in similar rapid and high antibody titres in both groups (median 512); cellular immunity changed little. At 48 months of age group 2 antibody concentrations remained well above protective levels though 2-fold lower than group 1; T-cell memory was readily detectable and similar in both groups.

Conclusions

An additional early measles vaccine given to children at 4 months of age induced a predominant CD4 T-cell response at 9 months and rapid development of high antibody concentrations after booster doses. However, antibody decayed faster in these children than in the group given primary vaccination at 9 months of age. Cellular responses after 9 months were generally insignificantly different.     

Socio-demographic determinants of timely adherence to BCG,Penta3, measles,and complete vaccination schedule in Burkina Faso

Objective

To identify the determinants of timely vaccination among young children in the North-West of Burkina Faso.

Methods

This study included 1665 children between 12 and 23 months of age from the Nouna Health and Demographic Surveillance System, born between September 2006 and December 2008. The effect of socio-demographic variables on timely adherence to the complete vaccination schedule was studied in multivariable ordinal logistic regression with 3 distinct endpoints: (i) complete timely adherence, (ii) failure, and (iii) missing vaccination. Three secondary endpoints were timely vaccination with BCG, Penta3, and measles, which were studied with standard multivariable logistic regression.

Results

Mothers’ education, socio-economic status, season of birth, and area of residence were significantly associated with failure of timely adherence to the complete vaccination schedule. Year of birth, ethnicity, and the number of siblings was significantly related to timely vaccination with Penta3 but not with BCG or measles vaccination. Children living in rural areas were more likely to fail timely vaccination with BCG than urban children (OR = 1.79, 95%CI = 1.24–2.58 (proximity to health facility), OR = 3.02, 95%CI = 2.18–4.19 (long distance to health facility)). In contrast, when looking at Penta3 and measles vaccination, children living in rural areas were far less likely to have failed timely vaccinations than urban children. Mother's education positively influenced timely adherence to the vaccination schedule (OR = 1.42, 95%CI 1.06–1.89). There was no effect of household size or the age of the mother.

Conclusions

Additional health facilities and encouragement of women to give birth in these facilities could improve timely vaccination with BCG. Rural children had an advantage over the urban children in timely vaccination, which is probably attributable to outreach vaccination teams amongst other factors. As urban children rely on their mothers’ own initiative to get vaccinated, urban mothers should be encouraged more strongly to get their children vaccinated in time.     

Seroprevalence of measles and rubella antibodies in pregnant women Haiti, 2012

Background

Haiti had set a national goal to eliminate measles and rubella, as well as congenital rubella syndrome (CRS) by 2010. A 2007–2008 nationwide measles and rubella vaccination campaign targeting 1–19 years, however, reached only 79% of the target population. To assess whether population immunity was adequate to support elimination, we conducted a national serosurvey.

Methods

We systematically selected 740 serum specimens collected from pregnant women in a 2012 national antenatal HIV sentinel serosurvey across four age strata: 15–19, 20–24, 25–29 and 30–39 years. Sera were tested for measles and rubella specific immunoglobulin G antibodies (IgG) using commercial immunoassays. We classified sera as seropositive, seronegative or indeterminate per manufacturer's instructions, and analyzed seroprevalence according to age strata, and rural or urban residence. We assessed immunity by estimating antibody concentrations in international units per milliliter (IU/mL) for seropositive and indeterminate sera. Measles IgG concentrations >0.12 IU/mL and rubella IgG concentrations >10 IU/mL were considered clinically protective.

Results

Of 740 sera, 696 (94.1%) were seropositive and 20 (2.7%) were indeterminate for measles IgG; overall 716 (96.8%) sera had IgG concentrations >0.12 IU/mL. For rubella IgG, 691 (93.4%) sera were seropositive and 1 (0.1%) was indeterminate; a total of 687 (92.8%) had IgG concentrations >10 IU/mL. Measles seropositivity varied across age strata (p = 0.003); seropositivity increased from 88.6% among 15–19 year olds to 98.4% among 30–39 year olds (Cochran–Armitage trend test ≤ 0.0001). Rubella seropositivity did not differ across age strata. There were no statistically significant differences in measles or rubella seropositivity by urban versus rural residence.

Conclusion

Despite previous low vaccination coverage for measles, results from this serosurvey indicate high levels of measles and rubella seropositivity in pregnant women, and contribute to the evidence for measles, rubella and CRS elimination from Haiti by the target date.     

Intervention effects from a social marketing campaign to promote HPV vaccination in preteen boys

Objectives

Adoption of human papillomavirus (HPV) vaccination in the US has been slow. In 2011, HPV vaccination of boys was recommended by CDC for routine use at ages 11–12. We conducted and evaluated a social marketing intervention with parents and providers to stimulate HPV vaccination among preteen boys.

Methods

We targeted parents and providers of 9–13 year old boys in a 13 county NC region. The 3-month intervention included distribution of HPV vaccination posters and brochures to all county health departments plus 194 enrolled providers; two radio PSAs; and an online CME training. A Cox proportional hazards model was fit using NC immunization registry data to examine whether vaccination rates in 9–13 year old boys increased during the intervention period in targeted counties compared to control counties (n = 15) with similar demographics. To compare with other adolescent vaccines, similar models were fit for HPV vaccination in girls and meningococcal and Tdap vaccination of boys in the same age range. Moderating effects of age, race, and Vaccines for Children (VFC) eligibility on the intervention were considered.

Results

The Cox model showed an intervention effect (β = 0.29, HR = 1.34, p = .0024), indicating that during the intervention the probability of vaccination increased by 34% in the intervention counties relative to the control counties. Comparisons with HPV vaccination in girls and Tdap and meningococcal vaccination in boys suggest a unique boost for HPV vaccination in boys during the intervention. Model covariates of age, race and VFC eligibility were all significantly associated with vaccination rates (p < .0001 for all). HPV vaccination rates were highest in the 11–12 year old boys. Overall, three of every four clinic visits for Tdap and meningococcal vaccines for preteen boys were missed opportunities to administer HPV vaccination simultaneously.

Conclusions

Social marketing techniques can encourage parents and health care providers to vaccinate preteen boys against HPV.     

High-dose vitamin A supplementation administered with vaccinations after 6 months of age: Sex-differential adverse reactions and morbidity

Background

WHO recommends vitamin A supplementation (VAS) at vaccination contacts after six months of age. The effect of this recommendation on mortality has not been evaluated.

Methods

We tested the effect of VAS at vaccination contacts on mortality in a randomised trial in Guinea-Bissau. In a subgroup within this trial we studied adverse reactions to VAS and whether VAS modified known adverse reactions to live and inactivated vaccines and general morbidity during the first month after supplementation overall and by sex. Children aged 6–17 months were randomised to VAS or placebo at the day of vaccination (day 0). We interviewed the caretaker, assessed the fontanel and measured temperature and local reaction at the injection site at home visits on day 1, 2, 3, 7, 14, 21, and 31. We defined systemic adverse reactions to inactivated and live vaccines as fever on day 1 and 2 and on 4–14 respectively. Clinical symptoms associated with increased intracranial pressure (ICP) on day 1 were considered possible adverse reactions to VAS.

Results

In 1673 children VAS had no overall effect on clinical symptoms associated with increased ICP (Relative Risk(RR) = 1.07 (95%CI: 0.85–1.35)). However, VAS was associated with such clinical symptoms in boys RR = 1.38 (1.00–1.91)) but not in girls (p = 0.03 for interaction between VAS and sex). VAS had no effect on fever after inactivated vaccines. VAS had no overall effect on fever after live vaccines (RR = 0.86 (0.53–1.39)), but tended to reduce the prevalence of fever in boys (RR = 0.58 (0.30–1.14)), but not in girls (RR = 1.37 (0.66–2.84)) (p = 0.09 for interaction between VAS and sex). VAS was associated with increased local reactions to measles vaccine in both sexes (RR = 3.65 (1.20–11.12)).

Conclusion

Adverse reactions were rare, mild and transient and may not in their own right cause concern. However, VAS caused sex-differential adverse reactions and may have sex-differential effects on adverse reactions to vaccines.     

Safety and immunogenicity of live-attenuated Japanese encephalitis SA 14-14-2 vaccine co-administered with measles vaccine in 9-month-old infants in Sri Lanka

Introduction

To facilitate introduction of live attenuated SA 14-14-2 Japanese encephalitis vaccine (LJEV) into the National Immunization Programme of Sri Lanka, we evaluated the safety and immunogenicity of co-administration of LJEV and measles vaccine at 9 months of age. Serum immune responses were evaluated post-vaccination on days 28, 180, and 365 using JE neutralization test and anti-measles IgG ELISA.

Results

278 infants received one dose of LJEV and measles vaccine. Of these, 257 were eligible for the per-protocol analysis. On Day 0, 14 infants (5.5%) were seropositive for JE, but none were seropositive for measles. At Day 28, seropositivity rates were 90.7% (95% CI, 86.4–93.9%) for JE and 84.8% (95% CI, 79.8–89.0%) for measles. The geometric mean titer for JE neutralizing antibodies was 111 (95% CI, 90–135), and the geometric mean concentration (GMC) for anti-measles IgG was 375 mIU/mL (95% CI, 351–400 mIU/mL). Over the next year, JE neutralizing antibody responses declined only slightly, with seropositivity at 87.4% (95% CI, 82.6–91.2%) at Day 365. In contrast, measles antibody levels continued to increase over time. Seropositivity for anti-measles IgG reached 97.2% (95% CI, 94.4–98.9%) at Day 365, and the GMC rose to 1202 mIU/mL (95% CI, 1077–1341 mIU/mL). Co-administration of LJEV and measles vaccine was also safe. Most adverse reactions were mild, and no serious adverse events were related to study vaccinations.

Conclusion

The safety and immunogenicity of LJEV co-administered with measles vaccine in Sri Lankan infants is similar to that seen in other populations, and our results support use of LJEV at 9 months of age. Live SA 14-14-2 vaccine is now prequalified by the WHO for use in infants in Asia, and other countries may wish to introduce LJEV to combat this devastating disease.     

No effect of oral polio vaccine administered at birth on mortality and immune response to BCG. A natural experiment

Background

WHO recommends oral polio vaccine at birth (OPV0) in polio endemic countries. During a period without OPV in Guinea-Bissau in 2004, we observed that not receiving OPV0 was associated with significantly decreased mortality in boys and better immune response to BCG vaccination. In 2007, whilst conducting a trial of BCG and vitamin A supplementation (VAS) at birth to low birthweight (LBW) children, OPV was again lacking for a short period. We used this natural experiment to test the previous observations.

Methods

In the trial LBW infants were randomised to early or delayed BCG and VAS or placebo at birth. We noted whether the children received OPV0 or not. We compared children who received No OPV0 with those who received OPV0 in the 2 months before and the 2 months after the period without OPV. Mortality was compared in Cox regression models providing adjusted hazard ratios (aHR); the immune response to BCG was assessed in Poisson models providing adjusted prevalence ratios (aPR).

Results

Ninety-nine children received No OPV0 and were compared with 243 children who received OPV0. No OPV0 was associated with insignificantly higher mortality during the first year of life, the aHR being 1.83 (95% CI: 0.93–3.61). The effect was similar in boys and girls. Overall, there was no significant association between No OPV0 and having a positive PPD response (aPR = 1.33 (0.64–2.78)) or a scar (aPR = 1.02 (0.93–1.11)) after BCG vaccination, though No OPV0 boys were more likely to develop a scar (aPR: 1.10 (1.01–1.20)).

Conclusions

The findings did not support our previous observation that not receiving OPV0 was associated with reduced mortality in boys. The findings weakly supported that OPV0 leads to a dampened response to simultaneously administered BCG vaccine in boys.     

Humoral immunogenicity to measles,rubella, and varicella-zoster vaccines in biliary atresia children

To investigate the humoral immune response to measles, rubella, and varicella-zoster virus (VZV) vaccines in biliary atresia (BA) children before liver transplantation, we conducted the cross-sectional designed study. Fifty BA children (age, 3.6 ± 0.2 years; 24 girls) who had not yet received liver transplantation, and another 150 healthy controls (age, 4.0 ± 0.1 years; 78 girls) were recruited into this study to evaluate their primary humoral immune response to measles, rubella, and VZV vaccines. All of these BA children (n = 50) and controls (n = 150) received one dose of measles, one dose of measles–mumps–rubella (MMR), and one dose of VZV vaccine before our assessment. Serum samples were collected at least 1 month after the vaccination and serum immunoglobulin G (IgG) antibody to measles, rubella, and VZV were then determined by qualitative enzyme-linked immune-sorbent assay. The prevalence of seropositive rate of measles IgG antibody (84% vs. 96.7%; P = 0.002), rubella (82.0% vs. 98.7%; P < 0.001), and VZV (74% vs. 95.3%; P < 0.001) were significantly different between BA children and the controls after regular measles, MMR, and VZV vaccination before 2 years of age. In those BA children with seronegative VZV antibody after vaccination, two had VZV infection after the liver transplantation. This study indicated that humoral immunity to rubella, measles and VZV vaccines are significantly lower in BA children than the normal population by standard vaccine schedule.     

Kinetics of maternally acquired anti-hepatitis A antibodies: Prediction of waning based on maternal or cord blood antibody levels

Background

Timing is critical for efficient hepatitis A vaccination in high endemic areas as high levels of maternal IgG antibodies against the hepatitis A virus (HAV) present in the first year of life may impede the vaccine response.

Objectives

To describe the kinetics of the decline of anti-HAV maternal antibodies, and to estimate the time of complete loss of maternal antibodies in infants in León, Nicaragua, a region in which almost all mothers are anti-HAV seropositive.

Methods

We collected cord blood samples from 99 healthy newborns together with 49 corresponding maternal blood samples, as well as further blood samples at 2 and 7 months of age. Anti-HAV IgG antibody levels were measured by enzyme immunoassay (EIA). We predicted the time when antibodies would fall below 10 mIU/ml, the presumed lowest level of seroprotection.

Results

Seroprevalence was 100% at birth (GMC 8392 mIU/ml); maternal and cord blood antibody concentrations were similar. The maternal antibody levels of the infants decreased exponentially with age and the half-life of the maternal antibody was estimated to be 40 days. The relationship between the antibody concentration at birth and time until full waning was described as: critical age (months) = 3.355 + 1.969 × log₁₀(Ab-level at birth). The survival model estimated that loss of passive immunity will have occurred in 95% of infants by the age of 13.2 months.

Conclusions

Complete waning of maternal anti-HAV antibodies may take until early in the second year of life. The here-derived formula relating maternal or cord blood antibody concentrations to the age at which passive immunity is lost may be used to determine the optimal age of childhood HAV vaccination.     

Duration of protection against hepatitis A for the current two-dose vaccine compared to a three-dose vaccine schedule in children

Background

Hepatitis A is mostly a self-limiting disease but causes substantial economic burden. Consequently, United States Advisory Committee for Immunization Practices recommends inactivated hepatitis A vaccination for all children beginning at age 1 year and for high risk adults. The hepatitis A vaccine is highly effective but the duration of protection is unknown.

Methods

We examined the proportion of children with protective hepatitis A antibody levels (anti-HAV ≥20 mIU/mL) as well as the geometric mean concentration (GMC) of anti-HAV in a cross sectional convenience sample of individuals aged 12–24 years, who had been vaccinated with a two-dose schedule in childhood, with the initial dose at least 5 years ago. We compared a subset of data from persons vaccinated with two-doses (720 EL.U.) at age 3–6 years with a demographically similar prospective cohort that received a three-dose (360 EL.U.) schedule and have been followed for 17 years.

Results

No significant differences were observed when comparing GMC between the two cohorts at 10 (P = 0.467), 12 (P = 0.496), and 14 (P = 0.175) years post-immunization. For the three-dose cohort, protective antibody levels remain for 17 years and have leveled-off over the past 7 years.

Conclusion

The two- and three-dose schedules provide similar protection >14 years after vaccination, indicating a booster dose is not needed at this time. Plateauing anti-HAV GMC levels suggest protective antibody levels may persist long-term.     

Co-administration of live measles and yellow fever vaccines and inactivated pentavalent vaccines is associated with increased mortality compared with measles and yellow fever vaccines only. An observational study from Guinea-Bissau

Background

Studies from low-income countries indicate that co-administration of inactivated diphtheria–tetanus–pertussis (DTP) vaccine and live attenuated measles vaccine (MV) is associated with increased mortality compared with receiving MV only. Pentavalent (DTP–H. Influenza type B–Hepatitis B) vaccine is replacing DTP in many low-income countries and yellow fever vaccine (YF) has been introduced to be given together with MV. Pentavalent and YF vaccines were introduced in Guinea-Bissau in 2008. We investigated whether co-administration of pentavalent vaccine with MV and yellow fever vaccine has similar negative effects.

Methods

In 2007–2011, we conducted a randomised placebo-controlled trial of vitamin A at routine vaccination contacts among children aged 6–23 months in urban and rural Guinea-Bissau. In the present study, we included 2331 children randomised to placebo who received live vaccines only (MV or MV + YF) or a combination of live and inactivated vaccines (MV + DTP or MV + YF + pentavalent). Mortality was compared in Cox proportional hazards models stratified for urban/rural enrolment adjusted for age and unevenly distributed baseline factors.

Results

While DTP was still used 685 children received MV only and 358 MV + DTP; following the change in programme, 940 received MV + YF only and 348 MV + YF + pentavalent. During 6 months of follow-up, the adjusted mortality rate ratio (MRR) for co-administered live and inactivated vaccines compared with live vaccines only was 3.24 (1.20–8.73). For MV + YF + pentavalent compared with MV + YF only, the adjusted MRR was 7.73 (1.79–33.4).

Conclusion

In line with previous studies of DTP, the present results indicate that pentavalent vaccine co-administered with MV and YF is associated with increased mortality.     

A serological survey of measles vaccine in a rural region of Eski?ehir in Turkey

We designed this longitudinal study as a response to measles outbreaks which occur occasionally in Eski?ehir in Turkey to investigate the incidence of primary and secondary vaccine failure. The investigation was conducted over two periods (December 1993 to October 1994 and April 1995 to October 1995). Two study groups were involved, infants aged 9–11 months and children aged 18 months to 9 y.During December 1993 to October 1994 prevaccination sera was collected from 35 infants aged 9–11 months and tested to determine if maternally derived antibodies were present. The infants were vaccinated and subsequently the 31 infants who could be traced were retested 30–40 d later to determine their response to vaccination.The following was done to determine whether seropositivity rates alter over time. The second group, a randomised sample of 117 children aged between 18 months to 9 y was chosen; all of whom had been previously vaccinated and who had no history of measles. Sera was taken and tested during December 1993 to October 1994 in order to determine whether seropositivity rates varied with time. During April 1995 to October 1995 out of all the children in both groups 123 children were retested. All sera samples were studied by an enzyme-lined immunosorbent assay (ELISA). Out of the 35 infants in group 1 only four (11.4%) had maternal antibody against measles on initial testing. Out of 31 infants followed up 30–40 d after vaccination (61.3%) were found to be seropositive for measles. In the second group, of the 117 previously vaccinated children ninety-three (71.5%) had measles IgG antibody. Seropositivity rates did not show significant difference with time after vaccination. There was no association between first and second screening seropositivity rates. We conclude that the presence of maternal antibody reduces the success of vaccination. These results suggest the vaccination policy in Turkey should be re-examined with a view to revision.     

Maternal pneumococcal capsular IgG antibodies and transplacental transfer are low in South Asian HIV-infected mother-infant pairs

Background

Our understanding of the mother-to-child transfer of serotype-specific pneumococcal antibodies is limited in non-immunized, HIV-positive women.

Methods

We compared geometric mean antibody concentrations (GMCs), geometric mean transplacental cord:maternal ratios (GMRs) and proportions of samples with protective antibody concentration (≥0.35 μg/ml) to serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F between 74 HIV-infected and 98 HIV-uninfected mother-infant pairs who had not received pneumococcal immunization in South Asia. Multivariable analysis was performed to assess the influence of HIV on protective antibody concentrations.

Results

HIV-infected mothers and their infants exhibited lower GMCs and GMRs than their uninfected counterparts. This was significant for all serotypes except maternal GMC to serotype 1 and GMR for serotype 6B. In multivariate analysis, HIV was significantly associated with reduced odds of having protective pneumococcal IgG levels; 56–73% reduction for 3 maternal serotypes (4, 5, 23F) and 62–90% reduction for all cord samples except serotype 6B.

Conclusions

Maternal HIV infection is associated with lower levels of maternal pneumococcal antibodies and disproportionately lower cord antibodies, relative to maternal antibodies, suggesting that HIV infection compromises transplacental transfer. Reassessment of maternal and/or infant pneumococcal immunization strategies is needed in HIV-infected women and their infants.     

Humoral responses to independent vaccinations are correlated in healthy boosted adults

Background

Roughly half of U.S. adults do not receive recommended booster vaccinations, but protective antibody levels are rarely measured in adults. Demographic factors, vaccination history, and responses to other vaccinations could help identify at-risk individuals. We sought to characterize rates of seroconversion and determine associations of humoral responses to multiple vaccinations in healthy adults.

Methods

Humoral responses toward measles, mumps, tetanus toxoid, pertussis, hepatitis B surface antigen, and anthrax protective antigen were measured by ELISA in post-immunization samples from 1465 healthy U.S. military members. We examined the effects of demographic and clinical factors on immunization responses, as well as assessed correlations between vaccination responses.

Results

Subsets of boosted adults did not have seroprotective levels of antibodies toward measles (10.4%), mumps (9.4%), pertussis (4.7%), hepatitis B (8.6%) or protective antigen (14.4%) detected. Half-lives of antibody responses were generally long (>30 years). Measles and mumps antibody levels were correlated (r = 0.31, p < 0.001), but not associated with select demographic features or vaccination history. Measles and mumps antibody levels also correlated with tetanus antibody response (r = 0.11, p < 0.001).

Conclusions

Vaccination responses are predominantly robust and vaccine specific. However, a small but significant portion of the vaccinated adult population may not have quantitative seroprotective antibody to common vaccine-preventable infections.     

Seroprevalence of measles,mumps and rubella among children in American Samoa, 2011, and progress towards West Pacific Region goals of elimination

Introduction

In line with the global goals for measles elimination, countries in the West Pacific Region (WPR) have set a goal to eliminate measles by 2012. Due to its contagiousness, high population immunity is needed for achieving and documenting measles elimination. We assessed population immunity to measles, mumps and rubella among first grade children in American Samoa (AS) through a seroprevalance study.

Methods

Using commercial indirect enzyme-linked immunosorbant IgG assays (Wampole Laboratories, Cranbury, NJ) we determined IgG antibodies against the measles, mumps, and rubella (MMR) viruses in sera collected from first grade students in AS in April–May 2011. Vaccination status was retrieved from the immunization cards. Factors associated with seropositivity of measles, mumps, and rubella were analyzed separately.

Result

Among 509 first grade students, measles, mumps, and rubella seroprevalence were 92%, 90%, and 93%, respectively. The proportions of first grade students with documented one or two doses of MMR vaccine were 93% and 84%, respectively. The vaccination status of 6% of the first graders was unknown and 1% was unvaccinated. Receiving two-doses of MMR vaccines was associated with high measles and mumps seropositivity (p < 0.01).

Conclusion

The high measles seroprevalence among children shows the progress by American Samoa towards measles elimination. Achieving and maintaining high two-dose MMR vaccine coverage in all age groups will aid in attaining the measles elimination status and prevent transmission of measles from potential imported measles cases from other countries.     

Comparing the cost-effectiveness of two- and three-dose schedules of human papillomavirus vaccination: A transmission-dynamic modelling study

Background

Recent evidence suggests that two doses of HPV vaccines may be as protective as three doses in the short-term. We estimated the incremental cost-effectiveness of two- and three-dose schedules of girls-only and girls & boys HPV vaccination programmes in Canada.

Methods

We used HPV-ADVISE, an individual-based transmission-dynamic model of multi-type HPV infection and diseases (anogenital warts, and cancers of the cervix, vulva, vagina, anus, penis and oropharynx). We conducted the analysis from the health payer perspective, with a 70-year time horizon and 3% discount rate, and performed extensive sensitivity analyses, including duration of vaccine protection and vaccine cost.

Findings

Assuming 80% coverage and a vaccine cost per dose of $85, two-dose girls-only vaccination (vs. no vaccination) produced cost/quality-adjusted life-year (QALY)-gained varying between $7900–24,300. The incremental cost-effectiveness ratio of giving the third dose to girls (vs. two doses) was below $40,000/QALY-gained when: (i) three doses provide longer protection than two doses and (ii) two-dose protection was shorter than 30 years. Vaccinating boys (with two or three doses) was not cost-effective (vs. girls-only vaccination) under most scenarios investigated.

Interpretation

Two-dose HPV vaccination is likely to be cost-effective if its duration of protection is at least 10 years. A third dose of HPV vaccine is unlikely to be cost-effective if two-dose duration of protection is longer than 30 years. Finally, two-dose girls & boys HPV vaccination is unlikely to be cost-effective unless the cost per dose for boys is substantially lower than the cost for girls.     

Diphtheria-tetanus-pertussis vaccine administered simultaneously with measles vaccine is associated with increased morbidity and poor growth in girls. A randomised trial from Guinea-Bissau

Background

Combined vaccination with diphtheria-tetanus-pertussis (DTP) and measles vaccine (MV) has been associated with increased mortality in observational studies. Among children missing MV and a dose of DTP and oral polio vaccine (OPV), we conducted a randomised trial of providing MV + DTP + OPV simultaneously, as currently recommended, or MV + OPV only, and examined the effect on morbidity and growth. We hypothesised that the MV + OPV group would experience less morbidity and grow better. Due to previous observations of sex differences in the non-specific effects of vaccinations, we analysed all data stratified by sex.

Methods

At the Bandim Health Project in Guinea-Bissau, 568 children who were due to receive MV and who were missing either DTP3 or DTP booster were enrolled in the study. A subgroup of 332 children was followed intensively to register adverse events and infections in the first month after vaccination. A subgroup of 276 children was followed every third month for a year to monitor growth. All children were followed for one year for infectious diseases, consultations, and hospitalisations.

Results

As expected, adverse events were more common in the MV + DTP + OPV group; diarrhoea and use of medication were increased among girls but not among boys (both p = 0.02, test of interaction between DTP and sex). Febrile disease with vesicular rash, as well as consultations and hospitalisations tended to be more common in the MV + DTP + OPV group than in the MV + OPV group; the hazard ratio (HR) for febrile disease with vesicular rash was 1.86 (1.00; 3.47). The strongest tendencies for more febrile diseases and hospitalisations in the MV + DTP + OPV group were found in girls. Overall, growth did not differ by randomisation group. However, results differed by sex. Girls in the MV + DTP + OPV group had a consistent pattern of worse z-scores for weight, height, and mid-upper-arm-circumference (MUAC) than girls in the MV + OPV group. The effect was opposite for boys, with boys in the MV + OPV group faring worse than those in the MV + DTP + OPV group, the interaction test for sex and DTP being significant for weight at 6 and 9 months, for MUAC at 12 months and for weight-for-height at 3 and 9 months after randomisation.

Conclusion

This is the first randomised trial of the non-specific effects of DTP and supports that these effects may be sex-differential and of clinical and anthropometric importance. Combined vaccination with DTP + MV + OPV may be detrimental for girls.     

Non-specific and sex-differential effects of vaccinations on child survival in rural western India

Background

Studies from Africa have suggested marked non-specific effects (NSEs) of routine vaccinations with effects on child survival. There have been few studies from Asia. We re-analyzed a study from Maharashtra, India, which had collected information on vaccinations during infancy and survival until 5 years of age.

Design

4138 children born between 1987 and 1989 were visited at home every three months to collect information on nutritional status and vaccinations. Since nutritional status was a determinant of time to vaccinations, we adjusted for nutritional status in the analyzes of the association between vaccinations and mortality.

Setting

45 contiguous villages in Shirur Administrative Block in Pune District.

Main outcome measures

Mortality rate ratios (MRR) for different vaccination status groups.

Results

The study area has male preferential treatment, but the female–male mortality ratio varied between age groups with different pre-dominant vaccines; it was high in the age group in which diphtheria–tetanus–pertussis (DTP) vaccine predominates and low in the age group in which measles vaccine (MV) is given. Children who followed the WHO recommended schedule of first BCG and then DTP vaccination were vaccinated earlier than other children (p < 0.01). Two-thirds of the children had received BCG and DTP out-of-sequence, i.e. BCG and DTP simultaneously or BCG after DTP. Children who received BCG and DTP simultaneously or BCG as most recent vaccination had significantly lower mortality than children having DTP as the most recent vaccination, the mortality rate ratio being 0.15 (0.03–0.70).

Conclusions

BCG out-of-sequence may be associated with lower mortality than DTP as the most recent vaccination. Given the public health implications, this possibility should be tested in randomized trials. Excess female mortality may also be related to vaccination policy.     

Seroconversions in unvaccinated infants: further evidence for subclinical measles from vaccine trials in Niakhar, Senegal

BACKGROUND: Increases in measles antibodies without rash-illnesses have been documented in previously vaccinated children exposed to measles cases. The phenomenon has been incompletely evaluated in young unvaccinated infants with immunity of maternal origin. METHODS: Monthly cohorts of newborns were prospectively randomized to vaccine and placebo control groups during a trial of high-titre vaccines in Niakhar, Senegal. Measles antibodies were assayed in blood samples of enrolled children collected at 5 months old, when controls received a placebo injection, and at 10 months, when the placebo group was given measles vaccine. Intensive prospective surveillance for measles was conducted throughout the trial. RESULTS: One-fifth (n = 53) of the placebo controls seroconverted, with known exposure to a measles case in only three of them. None of the seroconverters developed a measles-like rash. Sixteen-fold or greater increases in titres were noted in about one-quarter of them. Compared with placebo controls who did not seroconvert, seroconverters were more likely to have had exposure to a measles case and to travel, more likely to be boys than girls, and had significantly lower baseline antibody titres. Measles was endemic in the study area throughout the trial. Seroconversions did not adversely effect subsequent nutritional indices or mortality. CONCLUSIONS: Although laboratory errors and inadvertent injection of vaccine rather than placebo may have played some role, they do not fully explain the above observations, which are consistent with subclinical measles in the seroconverters. The possible role of subclinical measles in occult transmission, its potential effect on the type and duration of subsequent immunity, and its impact on response to primary vaccination need to be determined.