Non-specific effects of BCG and DTP vaccination on infant mortality: An analysis of birth cohorts in Ghana and Tanzania.

BACKGROUND: Vaccines may induce non-specific effects on survival and health outcomes, in addition to protection against targeted pathogens or disease. Observational evidence suggests that infant Baccillus Calmette-Guérin (BCG) vaccination may provide non-specific survival benefits, while diphtheria-tetanus-pertussis (DTP) vaccination may increase the risk of mortality. Non-specific vaccine effects have been hypothesized to modify the effect of neonatal vitamin A supplementation (NVAS) on mortality. METHODS: 22,955 newborns in Ghana and 31,999 newborns in Tanzania were enrolled in two parallel, randomized, double-blind, placebo-controlled trials of neonatal vitamin A supplementation from 2010 to 2014 and followed until 1-year of age. Cox proportional hazard models were used to estimate associations of BCG and DTP vaccination with infant survival. RESULTS: BCG vaccination was associated with a decreased risk of infant mortality after controlling for confounders in both countries (Ghana adjusted hazard ratio (aHR): 0.51, 95% CI: 0.38-0.68; Tanzania aHR: 0.08, 95% CI: 0.07-0.10). Receiving a DTP vaccination was associated with a decreased risk of death (Ghana aHR: 0.39, 95% CI: 0.26-0.59; Tanzania aHR: 0.19, 95% CI: 0.16-0.22). There was no evidence of interaction between BCG or DTP vaccination status and infant sex or NVAS. CONCLUSION: We demonstrated that BCG and DTP vaccination were associated with decreased risk of infant mortality in Ghana and Tanzania with no evidence of interaction between DTP or BCG vaccination, NVAS, and infant sex. Our study supports global recommendations on BCG and DTP vaccination and programmatic efforts to ensure all children have access to timely vaccination. CLINICAL TRIALS REGISTRATION: Ghana (Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000582055) and Tanzania (ANZCTR: ACTRN12610000636055).

[False beliefs about vaccines]. / Falsas creencias sobre las vacunas.

Vaccines are an essential tool for the prevention of infectious diseases. However, false ideas and rumours with no scientific foundation about their possible negative effects may dissuade people from being vaccinated, with the consequent risks for the health of the population. The objective of this article is to evaluate the origin and the arguments of some of the most frequent mistaken ideas and rumours about the possible adverse effects of vaccines. Some clearly established adverse effects are presented, as well as false beliefs about various vaccines and potential harm to health. Vaccines, like any drug, can cause adverse effects, but the possible adverse effects of vaccination programs are clearly lower than their individual (vaccinated) and collective benefits (those vaccinated and those who cannot be vaccinated for medical reasons). The possible adverse effects attributable to vaccines should be detected by powerful and well-structured pharmacovigilance systems.

Efficacy of Arsenicum album 30cH in preventing febrile episodes following DPT-HepB-Polio vaccination - a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Among the post-immunization adverse events, especially of Diphtheria-Pertusis-Tetanus (DPT), fever is a common systemic reaction. There is anecdotal support for the use of the homeopathic medicine Arsenicum album in preventing post-vaccination fever. The investigators intended to evaluate its efficacy in preventing febrile episodes following vaccination. METHODS: In the community medicine out-patient of Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, West Bengal, India, between August 2014 and January 2017, a double-blind, randomized, placebo-controlled trial was conducted on 120 children (verum: 60, placebo: 60) who presented for the 2nd and 3rd dose of DPT-HepB-Polio vaccination and reported febrile episodes following the 1st dose. Intervention used was Arsenicum album 30cH 6 doses or placebo (indistinguishable from verum), thrice daily for two subsequent days. Parents were advised to report any event of febrile attacks within 48h of vaccination, either directly or over telephone. RESULTS: The groups were comparable at baseline. Children reporting fever after the 2nd dose was 29.8% and 30.4% respectively for the homeopathy group and control group respectively [Relative Risk (RR)=1.008] with no significant difference (P=0.951) between groups. Again after the 3rd dose, children reporting fever were 31.5% and 28.3% respectively for the homeopathy group and control group respectively (RR=0.956) with no significant difference (P=0.719) between groups. CONCLUSION: Empirically selected Arsenicum album 30cH could not produce differentiable effect from placebo in preventing febrile episodes following DPT-HepB-Polio vaccination. [Trial registration: CTRI/2017/02/007939].

Evaluation of C-reactive protein as an inflammatory biomarker in rabbits for vaccine nonclinical safety studies.

INTRODUCTION: Inflammatory reactions are one of the potential safety concerns that are evaluated in the framework of vaccine safety testing. In nonclinical studies, the assessment of the inflammation relies notably on the measurement of biomarkers. C-reactive protein (CRP) is an acute-phase plasma protein of hepatic origin that could be used for that purpose in toxicity studies with rabbits. METHODS: To evaluate the utility of CRP as an additional inflammatory biomarker in adjuvant or vaccine toxicity studies, rabbits were injected on Day 0 with saline, aluminium phosphate, aluminium hydroxide, Adjuvant System (AS)01, AS03, AS15, or diphtheria-tetanus-whole cell pertussis-hepatitis B vaccine (DTPw-HB). Body weights, haematology parameters, CRP and fibrinogen levels were measured daily up to Day 7. Macroscopic changes at the injection site were also evaluated up to Day 7. At Day 7, a histopathological examination of the injection site was performed. RESULTS: Like fibrinogen, CRP levels rapidly increased after the injection of Adjuvant Systems or DTPw-HB, peaking at Day 1, and returning to baseline in less than a week. The magnitude of the CRP increase was consistently higher than that of fibrinogen with a larger fold increase from background, providing a more sensitive evaluation. The number of circulating heterophils was also increased on Day 1 after the injection of Adjuvant Systems or DTPw-HB. The highest increases in CRP levels were observed after the injection of DTPw-HB or AS03, and were also associated with the persistence of mixed inflammatory cell infiltrates (including heterophils) at the injection sites on Day 7. No increases in CRP levels and in circulating heterophils were observed after injection of the aluminium salt adjuvants. DISCUSSION: Our study supports the use of CRP as an accurate biomarker of acute inflammation in rabbits for vaccine toxicity studies and highlights an association between increased CRP levels and the recruitment of heterophils.

The effect of vitamin A supplementation and diphtheria-tetanus-pertussis vaccination on parasitaemia in an experimental murine malaria model.

BACKGROUND: Vitamin A supplementation (VAS) decreases overall child mortality in low-income countries. For logistical reasons, VAS has been linked to routine childhood immunizations. However, several recent studies have indicated that VAS may increase mortality and morbidity from infectious diseases when given with the diphtheria-tetanus-pertussis (DTP) vaccine. The immunological effects of combining the 2 treatments are unknown. METHODS: We studied the effect of treating C57BL/6 mice with VAS and DTP, 1 week prior to infection with Plasmodium berghei ANKA. The progression of disease was monitored through parasite load and time to death. RESULTS: We found significantly higher levels of parasitaemia in VAS/DTP-treated mice than in control mice (crude geometric mean parasitaemia ratio 2.02 (1.08-3.76), p = 0.03). There was no effect of administering either VAS or DTP alone, indicating that the increase in parasitaemia was due to a synergistic effect of VAS and DTP (p for interaction = 0.02). The effect of VAS/DTP on levels of parasitaemia was modified by the specific parasite variant used. No effect was observed on time to death. CONCLUSION: Our results indicate that VAS/DTP can negatively influence the outcome of malaria infection in mice, adding to the concerns about simultaneous VAS and DTP administration to children in low-income, malaria endemic countries.

Should infant girls receive micronutrient supplements?

BACKGROUND: We have proposed the hypothesis that the combination of vitamin A supplementation and diphtheria-tetanus-pertussis (DTP) vaccination may be associated with increased mortality in girls. Recent zinc/folic acid (FA) and iron supplementation trials did not find any beneficial effects on mortality. We reviewed the studies for evidence of a negative interaction between zinc/folic acid/iron and DTP vaccination in girls. METHODS: Based on the published papers, we calculated age- and sex-specific mortality estimates. No vaccination status data were provided. RESULTS: Both zinc/FA and iron seemed to have a sex- and age-differential effect, the effect being less beneficial in the youngest girls who are most likely to have DTP vaccine as their most recent vaccination. CONCLUSIONS: Like vitamin A, zinc/FA and iron may not benefit the youngest girls. The question is whether this is inherent in girls or due to an interaction with some environmental factor like DTP.

The effect of vitamin A supplementation administered with missing vaccines during national immunization days in Guinea-Bissau.

BACKGROUND: WHO recommends high-dose Vitamin A supplementation (VAS) at vaccination contacts after 6 months of age. It has not been studied whether the effect of VAS on mortality depends on the type of vaccine. We have hypothesized that VAS administered with measles vaccine (MV) is more beneficial than VAS with diphtheria-tetanus-pertussis (DTP) vaccine. We assessed the effect of VAS administered with different vaccines during national immunization days (NIDs). METHODS: In 2003, VAS was distributed during NIDs in Guinea-Bissau. Children 6 months or older were given VAS, and if they were missing vaccines, these were often given as well. We compared survival between children who had received VAS alone, VAS with DTP or DTP + MV, or VAS with MV. We also compared the survival between participants and non-participants. We followed 6- to 17-month old children until 18 months of age and analysed survival in Cox models. RESULTS: Twenty of 982 VAS-recipients died during follow-up. The mortality rate ratio (MRR) for VAS with DTP + MV or VAS with DTP was 3.43 (1.36-8.61) compared with VAS only. There were no deaths among those who received VAS with MV alone (P = 0.0005 for homogeneity of VAS effects). Children who received VAS with DTP had higher mortality than non-participants who did not receive VAS [MRR = 3.04 (1.31-7.07)]. CONCLUSION: The study design does not allow for definite conclusions. However, the results are compatible with our a priori hypothesis that VAS is more beneficial when given with MV and potentially harmful when given with DTP. Randomized trials testing the impact on mortality of the current WHO policy seem warranted.

Vitamin A supplements are well tolerated with the pentavalent vaccine.

The Expanded Programme on Immunisation provides an opportunity to deliver vitamin A supplements to young infants in order to improve their vitamin A status. However, concerns have been raised about the safety of administering high dose vitamin A supplements to infants less than 6 months of age in developing countries. A randomized controlled trial was carried out by the Kintampo Health Research Centre to assess the safety and immunogenicity of administering 15 mg retinol equivalent (RE)1 vitamin A alongside the pentavalent "diphtheria-polio-tetanus-Haemophilus influenzae b-hepatitis B vaccine" at 6, 10 and 14 weeks of age. All mothers received a post-partum supplement of 120 mg RE vitamin A as per national policy. Mothers of infants who had been vaccinated were visited 24 h after vaccination to assess the side effects of the vaccine. They were also interviewed about adverse events which may have occurred in the past 4 weeks since the child was vaccinated. There were significantly fewer reports of illnesses and fever in infants who had been given vitamin A compared to infants in the control group. The pentavalent vaccine was found to be tolerable when administered with vitamin A according to the WHO/EPI schedule for infant immunisation at 6, 10 and 14 weeks. There were few complaints made by the mothers of the children which were not thought to be related to giving vitamin A with the vaccines. There were six deaths in the trial, five in the intervention group and one in the control RR 4.65 (0.55-39.5), p = 0.12. Due to the high point estimate of 4.65, we wish to urge caution in administering high doses of vitamin A to young infants with the pentavalent vaccine at 6, 10 and 14 weeks of age.

Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age.

BACKGROUND: The effect of vitamin A supplementation (VAS) at birth on subsequent vitamin A status has not been studied. OBJECTIVE: The objective was to study the effect of 50,000 IU vitamin A administered with BCG vaccine at birth on vitamin A status in both sexes. DESIGN: Within a randomized placebo-controlled trial of VAS, we obtained blood from 614 children at 6 wk of age and from 369 mother-infant pairs at 4 mo of age. We assessed vitamin A status on the basis of serum retinol-binding protein (RBP) and measured serum C-reactive protein to monitor for concurrent infections. RESULTS: RBP concentrations indicated vitamin A deficiency in 32% of the children at age 6 wk and in 16% at age 4 mo. VAS was not associated with higher RBP concentrations overall or in either sex. However, the effect of VAS varied with maternal education (P for interaction = 0.004): At age 6 wk, VAS was associated with higher (9%; 95% CI: 2, 17%) RBP concentrations in children of noneducated mothers but not in children of educated mothers. Overall, RBP concentrations increased between 6 wk and 4 mo of age. The increase correlated inversely with the number of diphtheria-tetanus-pertussis (DTP) vaccines received in the interval (P = 0.009), particularly in girls (P for interaction = 0.01) and in vitamin A recipients (P = 0.01). CONCLUSIONS: Overall, VAS at birth had no effect on vitamin A status. However VAS may temporarily improve vitamin A status in the subgroup of children of noneducated mothers. In vitamin A recipients, subsequent DTP vaccines affected vitamin A status negatively. The main trial was registered at clinicaltrials.gov as NCT00168597.

Uso do bioterápico preparado a partir do precipitado da vacina tríplice na prevençäo dos efeitos adversos locais produzidos pela adjuvante hidróxido de alumínio existente no precipitado da vacina / Use of the biotherapic prepared to set out of the precipited triple vaccine on prevent of the adverse effects make of adjuvant allumin hidroxid exists at the vaccin precipited

Dentro do capítulo conhecido como cinética de eliminaçäo, fizemos o presente estudo preparando medicamento a partir do precipitado da vacina tríplice na 30 CH, com o objetivo de verificar a açäo preventiva sobre os efeitos adversos locais produzidos pelo adjuvante hidróxido de alumínio existente no precipitado da vacina.

Uso do hidróxido de alumínio (6CH) na prevençäo dos efeitos adversos locais da vacina tríplice (DPT) / Use of allumin hidroxide 6CH to prevent adverse effects of the triple vaccin

Admitindo que a açäo de efeitos adversos locais da vacina tríplice seja provocada pelo hidróxido de alumínio e considerando o conceito homeopático de cinética de eliminaçöes, o presente trabalho busca utilizar o proprio hidróxido de alumínio, porém dinamizado na 6CH como preventivo dos efeitos adversos provocados pela própria substância. Näo encontrando resultados significativos, o autor sugere a continuaçäo do trabalho utilizando outros parâmentros.

Effects of diphtheria-tetanus-pertussis or tetanus vaccination on allergies and allergy-related respiratory symptoms among children and adolescents in the United States.

BACKGROUND: Findings from animal and human studies confirm that diphtheria and tetanus toxoids and pertussis (DTP) and tetanus vaccinations induce allergic responses; associations between childhood vaccinations and subsequent allergies have been reported recently. OBJECTIVE: The association of DTP or tetanus vaccination with allergies and allergy-related respiratory symptoms among children and adolescents in the United States was assessed. METHODS: Data were used from the Third National Health and Nutrition Examination Survey on infants aged 2 months through adolescents aged 16 years. DTP or tetanus vaccination, lifetime allergy history, and allergy symptoms in the past 12 months were based on parental or guardian recall. Logistic regression modeling was performed to estimate the effects of DTP or tetanus vaccination on each allergy. RESULTS: The odds of having a history of asthma was twice as great among vaccinated subjects than among unvaccinated subjects (adjusted odds ratio, 2.00; 95% confidence interval, 0.59 to 6.74). The odds of having had any allergy-related respiratory symptom in the past 12 months was 63% greater among vaccinated subjects than unvaccinated subjects (adjusted odds ratio, 1.63; 95% confidence interval, 1.05 to 2.54). The associations between vaccination and subsequent allergies and symptoms were greatest among children aged 5 through 10 years. CONCLUSIONS: DTP or tetanus vaccination appears to increase the risk of allergies and related respiratory symptoms in children and adolescents. Although it is unlikely that these results are entirely because of any sources of bias, the small number of unvaccinated subjects and the study design limit our ability to make firm causal inferences about the true magnitude of effect.

Effect of local massage on vaccination: DTP and DTPa.

We previously demonstrated that local massage for one minute can enhance immunogenicity of diphtheria, tetanus, and whole-cell pertussis (DTPw) vaccination. This study further analyzes the effects of more intense local manipulation on infants after DTPw and DTPa (diphtheria, tetanus, and acellular pertussis) vaccination. A total of 808 infants aged two months were recruited to be vaccinated with either DTPw or DTPa. Vaccinees in both groups were further divided into two groups; those receiving local manipulation (massage and hot packing after vaccinations) and those receiving only vaccinations. Results showed that safety profiles were largely similar between those who had local manipulation following vaccination and those without. The only significant difference was more frequent local reactions including pain and swelling following the first two doses in both the DTPa and DTPw groups receiving manipulation compared with the groups not receiving manipulation. Serologic tests revealed that local manipulation had no significant effect on antibody response to pertussis toxin and filamentous hemagglutinin, and diphtheria and tetanus toxins. The effect of local massage on DTPw was related to the intensity of local massage. Too vigorous a local manipulation caused adverse local reactions and no beneficial effect on antibody response. As for the infants receiving DTPa and local massages for two minutes with hot packing, no significant effect on either the reactogenicity or immunogenicity was found.

Local massage after vaccination enhances the immunogenicity of diphtheria-tetanus-pertussis vaccine.

The effect of local massage on adverse reactions and immunogenicity of diphtheria-tetanus-pertussis vaccine was investigated. After diphtheria-tetanus-pertussis vaccination 327 infants were either massaged or not, and adverse reactions were evaluated. Local pain and fever were more frequent in the massage group. The extra febrile episodes from massage were mild (38-39 degrees C). For evaluation of the antibody responses, 124 infants were recruited into massage or nonmassage cohorts and antibody production was measured at 2, 6, 7, 18 and 19 months of age, respectively. Subjects in the massage group developed significantly higher antibodies against filamentous hemagglutinin at 6 and 7 months of age, pertussis toxin at 6, 7, 18 and 19 months of age, pertussis agglutinogen at 18 and 19 months of age and those in the nonmassage group. Local massage after diphtheria-tetanus-pertussis vaccination was associated with better immunogenicity and more adverse reactions, including low grade fever and local pain, which were mild and not particularly disturbing.

Can Haemophilus influenzae type b-tetanus toxoid conjugate vaccine be combined with diphtheria toxoid-pertussis vaccine-tetanus toxoid?

OBJECTIVE: To assess the side effects and immune responses after three serial doses of PRP-T vaccine (a Haemophilus influenzae type b [Hib]-tetanus toxoid conjugate vaccine) given concurrently or mixed with adsorbed DPT vaccine (diphtheria toxoid-pertussis vaccine-tetanus toxoid). DESIGN: Multicentre randomized controlled trial. SETTING: Four public health units in western Canada. PARTICIPANTS: Healthy infants 8 to 15 weeks old at entry who were able to receive routine primary vaccinations. Of 444 infants enrolled, 433 (98%) completed the study. INTERVENTIONS: All infants received PRP-T and DPT vaccines at 2, 4 and 6 months of age: half received them mixed in one injection and the others as separate, bilateral injections. MAIN OUTCOME MEASURES: Side-effects 24 and 48 hours after each dose and serologic responses to each vaccine component. RESULTS: Follow-up was obtained after all 1312 vaccinations. Fever was infrequent in the two treatment groups. Local adverse effects of the PRP-T vaccine were infrequent and mild (e.g., redness was noted in 5.9% of cases and the area of redness was more than 2.5 cm in diameter in 0.8%). The incidence rate of local effects of the DPT-containing vaccines was the same in the two groups except for tenderness, which was more frequent in the group given the mixed vaccine (26.6% v. 17.9%, p < 0.001). Serologic data were available for 97% of the subjects. After the three doses 98.1% of the subjects had a PRP antibody level of 0.15 micrograms/mL or more, and 87.9% had a level of 1.0 micrograms/mL or more, both levels compatible with protection against Hib. Responses to PRP-T were comparable between the treatment groups as were responses to the diphtheria and tetanus toxoids. Pertussis agglutinin titres were reduced after administration of one of two PRP-T lots mixed with DPT vaccine, but responses to four other pertussis antigens were not impaired. CONCLUSION: PRP-T vaccine is well tolerated and immunogenic. Combined PRP-T and DPT vaccines performed satisfactorily and may be the preferred method of administration.