Diphtheria–tetanus–pertussis vaccine: past, current & future

The diphtheria–tetanus–pertussis (DTP) vaccine can prevent diphtheria, tetanus and pertussis. The component antigens of the DTP vaccine had long been monovalent vaccines. The pertussis vaccine was licensed in 1914. The same year, the mixtures of diphtheria toxin and antitoxin were put into use. In 1926, alum-precipitated diphtheria toxoid was registered, and in 1937 adsorbed tetanus toxoid was put on the market. The development of numerous effective DTP vaccines quickly stimulated efforts to combine DTP with other routine vaccines for infants. This overview covers the most important information regarding the invention of DTP vaccines, their modifications and the needs that should be focused on in the future.

Estimation of production consistency of diphtheria, tetanus, and pertussis components of the DTP vaccine using Shewhart charts

The Russian Federation puts special emphasis on vaccination-related issues, in accordance with the WHO recommendations. The fact that vaccination, in particular with the diphtheria, tetanus, and pertussis vaccine (DTP vaccine), covers large population groups, accounts for the relevance of research aimed at improving the quality of vaccines. One of the ways to produce vaccines of assured quality is to maintain consistent manufacturing processes that ensure consistency of product characteristics. The stability of the technological processes may be assessed using Shewhart charts. The aim of the study was to assess the production consistency of diphtheria, tetanus, and pertussis components of DTP vaccine using Shewhart control charts. Materials and methods: the study used data from 60 batch summary protocols of a Russian-produced DTP vaccine that were submitted to the Testing Centre of the Scientific Centre for Expert Evaluation of Medicinal Products from September 2017 until April 2020. The study assessed one of the main vaccine quality characteristics—specific (protective) activity of diphtheria, tetanus, and pertussis components. Shewhart charts for the diphtheria and tetanus components were constructed based on the manufacturer’s summary protocols, while Shewhart charts for the pertussis component were constructed based on both summary protocols and the results obtained by the Testing Centre during certification of the product batches. The Shewhart charts were used in accordance with the national standards GOST R 50779.42-99 and GOST R ISO 7870-2-2015. Results: a retrospective analysis of R- and X-charts covering a 2.5-year period revealed some characteristic trends in special-cause criteria. The most alarming situation was observed for the production of the diphtheria component. The technological processes were somewhat safer in the case of the tetanus and pertussis components. The production process lacked due statistical control, which is confirmed by the lack of correlation between the results of the pertussis component activity assessment obtained by the manufacturer and the Testing Centre. Conclusions: during the analysed period, the production of the diphtheria, tetanus, and pertussis components of the DTP vaccine was not always consistent. This highlights the need to conduct research aimed at standardisation of both production processes and control test conditions.

Seasonal modulation of antibody response to diphtheria-tetanus-pertussis vaccination in infants: a cohort study in rural Gambia

Background In rural Gambia, rates of malnutrition and infection are higher during the annual rainy/‘hungry’ season (June–October) in comparison to the dry/‘harvest’ season (November–May). The effects of this seasonal pattern on an infant’s immune development and their capacity to respond to childhood vaccinations remain unclear. The aim of the current analysis was to determine whether antibody responses to diphtheria-tetanus-pertussis (DTP) vaccinations in infants differ between seasons. Methods Infants received the DTP vaccine at 8, 12 and 16 weeks of age and antibody titres were measured in blood samples collected at 12 (n = 710) and 24 (n = 662) weeks of age. Mean DTP antibody titres, adjusted for maternal and infant confounders, were compared by t-tests and the effect sizes of the mean differences were calculated between seasons at mid-gestation (20 weeks gestation) and first vaccination (8 weeks of infant age). Results A smaller number of infants received their first vaccination during the rainy/hungry season months compared to the dry/harvest season (n = 224 vs. n = 486). At 12 weeks, infants vaccinated during the rainy/hungry season had lower weight-for-length Z-scores (p = 0.01) and were more likely to be anaemic (p < 0.001). Their mothers, however, were pregnant mostly during the dry/harvest season, had higher weight gain (p < 0.001) and were less likely to be anaemic during pregnancy (p < 0.001). At 12 weeks, infants vaccinated during the rainy/hungry season had significantly higher mean diphtheria, tetanus and pertussis antibody titres; by 62.3, 16.9 and 19.7%, respectively (all, p < 0.001). However, at 24 weeks, they had lower mean anti-diphtheria titres (by 20.6%, p < 0.001) compared with infants vaccinated during the dry/harvest season, and no differences were observed in mean tetanus and pertussis antibody titres by vaccination season. Conclusions Infant antibody response to the primary dose of the DTP vaccine was influenced by both season of pregnancy and infancy, although effects were diminished following three doses. Environmental exposures, including nutrition, to both the mother and infant are hypothesised as likely drivers of these seasonal effects.

Urinary screening for detection of renal abnormalities in asymptomatic pre-school children referred to Ardabil city health centers from 2016 to 2017

Background: Urinary screening for detection of proteinuria, hematuria, and pyuria for early diagnosis curable or preventable renal disease in three decade has been considered. The aim of this study was urinary screening for Detection of renal abnormalities in asymptomatic pre-school children referred to health center in Ardabil city from 2016 to 2017.Methods: This was a cross-sectional descriptive study that has been done on urine specimens of 350 children who referred to Ardabil city health center to injection DTP vaccine from April 2016 to Sep 2017. In these infants, proteinuria, hematuria, pyuria and urinary casts were examined and abnormal finding were referred to future investigation to nephrologist. Information was collected and analyzed by statistical methods in SPSS version 21.Results: A total of 350 children were enrolled in the study. There were 196 (56%) boys and 154 (44%) girls. The prevalence of urinary abnormalities in all children was 8.3%. Of all urinary abnormalities, proteinuria and hematuria were detected in 12 children (3.44 %). Of all infants, 9 children (2.57%) had pyuria. Also, 6 children (1.8%) had urinary casts that of them two cases had acid ureic cast and four cases had calcium oxalate cast.Conclusions: This study showed that the prevalence of urinary abnormalities in Ardabil city children was similar to other studies in other country or cities. The reasons of this may be different in race and ethnic. We suggest that routine urinalysis should be part of screening of children at the school entry in Ardabil.

Rate of the occurrence of adverse events in preschool children after vaccination at the Health Care Center in Inđija

Introduction: An adverse event following immunization is any undesirable medical occurrence that follows immunization, and which does not necessarily have a causal relationship with the usage of the vaccine. The aim of this study was to determine the rate of occurrence of adverse events in preschool children, after vaccination at the Primary Health Care Center in Inđija. Material and methods: Data were used from the medical and administrative documentation of the Pediatrics Department in Inđija. The study covered a period of 11 years and during this period 4,273 children were vaccinated, and 70,558 doses of vaccines were administered. Results: 13 cases of severe adverse reactions to a vaccine were registered, with a rate of 18.4:100,000 vaccine doses. There were 6 severe adverse reactions to the DTP vaccine per 8,180 administered doses of this vaccine, which was a rate of 73.3:100,000 doses of the DTP vaccine. There were 7 cases of severe adverse reactions to the MMR vaccine per 8,505 administered doses of the MMR vaccine, which was a rate of 82.3:100,000 doses of MMR vaccine. The overall rate of adverse reactions in the form of mumps was 47.0:100,000 doses of the MMR vaccine, in the form of rubella rash it was 11.7:100,000 doses of the MMR vaccine and the rate of adverse allergic reactions to the MMR vaccine was 23.5:100,000 doses of the MMR vaccine. According to our results, there were two cases of adverse reactions in the form of allergic reaction, to all vaccines administered, which was the rate of 3:100,000. Conclusion: This study confirms the very rare occurrence of severe adverse reactions to vaccination and speaks in favor of a far greater benefit from vaccination as compared to the risk of an adverse reaction to vaccination.

The maternal antibody against diphtheria, tetanus and pertussis showed distinct regional difference in China

Background Passive transferred antibodies to the fetus play an essential role on protecting neonates and young infants until infant vaccination is more efficacious. However, very little is known about the discrepancy of DTP vaccine associated antibodies level in neonates from different economic areas in China. Methods In 2018, 200 neonates hospitalized in Shunyi Women and Children’s Hospital in Beijing, and 238 neonates hospitalized in Qianjiang Central Hospital located in the southwestern mountainous areas were included in this study. Antibodies specific for the antigens covered by DTP vaccine were determined using ELISA Kits (Euroimmun, Lübeck, Germany). The cut off value of ≥0.1 IU/ml (anti-diphtheria, anti-Dtx), > 0.1 IU/ml (anti-tetanus, anti-Ttx) and > 40 IU/ml (anti-pertussis toxin, anti-Ptx) were used to assess the percentage of protected neonates, respectively. Results The antibody levels in the neonates from Qianjiang (0.04 IU/ml for anti-Dtx IgG and 0.07 IU/ml for anti-Ttx IgG) were significantly lower than those from Shunyi (0.12 IU/ml for anti-Dtx IgG and 0.18 IU/ml for anti-Ttx IgG). The prevalence of protective anti-Dtx and anti-Ttx IgG were lower in the neonates from Qianjiang (7.1% for anti-Dtx IgG and 7.6% for anti-Ttx IgG) than in those from Shunyi (30.5% for anti-Dtx and 38.5% for anti-Ttx). The neonates from Qianjiang also had lower detectable rate of anti-Dtx (57.5%) and anti-Ttx IgG (55.8%) than neonates from Shunyi (97.5% for anti-Dtx and 71.0% for anti-Ttx). However, the detectable rate of anti-Ptx IgG in neonates from Qianjiang (39.9%) was higher significantly than in those from Shunyi (30.5%). Two neonates from Qianjiang have anti-PT IgG ≥100.0 IU/ml, which suggested that their mothers have a recent pertussis course. Conclusions The regional discrepancy of the protective antibody rates might be caused by different vaccine coverage and pertussis exposure, which suggested the importance of Tdap booster immunization for pregnant women or women at childbearing age, those living undeveloped areas in particular.

Selection bias introduced by informative censoring in studies examining effects of vaccination in infancy

Background Many studies have examined ‘non-specific’ vaccine effects on infant mortality: attention has been particularly drawn to diphtheria-tetanus-pertussis (DTP) vaccine, which has been proposed to be associated with an increased mortality risk. Both right and left censoring are common in such studies. Methods We conducted simulation studies examining right censoring (at measles vaccination) and left censoring (by excluding early follow-up) in a variety of scenarios in which confounding was and was not present. We estimated both unadjusted and adjusted hazard ratios (HRs), averaged across simulations. Results We identified scenarios in which right-censoring at measles vaccination was informative and so introduced bias in the direction of a detrimental effect of DTP vaccine. In some, but not all, situations, adjusting for confounding by health status removed the bias caused by censoring. However, such adjustment will not always remove bias due to informative censoring: inverse probability weighting was required in one scenario. Bias due to left censoring arose when both health status and DTP vaccination were associated with mortality during the censored early follow-up and was in the direction of attenuating a beneficial effect of DTP on mortality. Such bias was more severe when the effect of DTP changed over time. Conclusions Estimates of non-specific effects of vaccines may be biased by informative right or left censoring. Authors of studies estimating such effects should consider the potential for such bias and use appropriate statistical approaches to control for it. Such approaches require measurement of prognostic factors that predict censoring.

Lessons Learned from the Testing of Neonatal Vitamin A Supplementation

A total of 12 trials have tested the effect of neonatal vitamin A supplementation (NVAS) on mortality. Overall, NVAS had no effect on mortality, but results were heterogeneous. Two competing hypotheses have been put forward to explain the divergent effects: A) NVAS works by preventing vitamin A deficiency (VAD) and not all countries have VAD; B) NVAS interacts negatively with subsequent diphtheria-tetanus-pertussis (DTP) vaccine, increasing mortality in females; in countries with low DTP coverage NVAS may have a beneficial effect. Only hypothesis A was tested in a recent meta-analysis; there is no strong empirical support for hypothesis A and it would not explain observed negative effects in some settings. Hypothesis B accounts for most observations. However, so far it has only been tested properly in a few trials. If hypothesis B is correct, it has major consequences for the understanding of the effects of vitamin A, and for the VAS policy in older children. As a WHO priority, the DTP coverage is bound to increase, and therefore hypothesis B urgently needs to be tested.

Estimation of Consistency of Production of the Pertussis Component of DTP Vaccine in Terms of Immunogenic Activity and Specific Safety Using Shewhart Charts

WHO experts attribute the resurgence of whooping cough to the wide use of acellular pertussis vaccines (aPs) as components of combination products. In this regard, WHO encourages countries that have not yet switched to the use of aPs to continue to use whole-cell pertussis vaccines (wPs) for primary vaccination. The experience of using pertussis vaccines has shown that companies do not always produce highly efficacious products. The use of statistical methods of samples quality control helps to ensure consistency of the technological process, which results in the production of more homogeneous products, and rules out the possibility of producing low-quality products. This paper presents the results of retrospective evaluation of the consistency of the wP (as a pertussis component of the DTP vaccine) production using Shewhart control charts. It was shown that at some points in time during the analyzed period from January 2017 until March 2018 the technological process of the company lacked proper statistical control. This increased the risk of producing non-uniform and defective products. In order to improve the quality and consistency of pertussis component batches, the company’s quality control and quality assurance services should make extensive use of Shewhart charts on a real-time basis.

Population Immunity to Diphtheria and Tetanus in the Republic of Belarus Following Long-Standing Vaccination

Study results of IgG to diphtheria and tetanus in 785 residents aged from 1 to 76 years old from different regions of the Republic of Belarus (in 2017) in long-term (since 1996) immunization schedule: at 3, 4, 5 and at 18 months old – DTP vaccine, at 6 years old – DT, at 11 years old – Diphtheria toxoid, at 16 years old, 26 years old and every following 10 years –Td or Diphtheria toxoid are presented. The antibody concentration was measured by Virion/Serion kits (Germany) and evaluated in accordance with the international standard: less than 0.01 IU/ml – individual is susceptible, 0.01–0.09 IU/ml – levels of antitoxin giving some degree of protection, 0.1 – < 1 IU/ml – protective level of circulating antitoxin, ≥ 1.0 IU/ml – a level of antitoxin giving long-term protection. It was shown that the proportion of immune individuals against diphtheria and tetanus (with antibodies ≥ 0.01 IU/ml) was 96.7% (CI 95.4 ÷ 97.9) and 99.5% (CI 99.0 ÷ 100,0), respectively, and was quite high in all the population age groups – from 87.7 to 100% for diphtheria and from 96.5 to 100% for tetanus. In seropositive individuals IgG were presented mainly in protective and highly protective (≥ 0.1 IU/ml) titers: for diphtheria 93.7% – in 1–14 years old; 88.7% – in 15–19 years old; 78.4% – in 20–76 years old and for tetanus 100.0% – in 1–14 years old; 100.0% – in 15–19 years old; 99.3% – in 20–76 years old. Comparison of the current and previous studies results (in 1989–1994 – during the outbreak of diphtheria, in 1998–2001 – after the mass immunization campaign, in 2004 – in the context of continuous single cases of diphtheria registration in adults) had shown that the data of 2017 demonstrated the highest population immunity level to diphtheria and to tetanus in the last 30 years of observation.