Non-specific Effects Of Vaccines Research Articles

Non-specific effects of vaccines – relevant to pregnant women?

Non-specific effects of vaccines – relevant to pregnant women?

Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines.

The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

Cohort Profile: Childhood morbidity and potential non-specific effects of the childhood vaccination programmes in the Nordic countries (NONSEnse): register-based cohort of children born 1990–2017/2018

PurposeThe aim of the NONSEnse project is to investigate the non-specific effects of vaccines and immunisation programmes on the overall health of children by using information from the extensive nationwide...

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

BackgroundVaccines 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. Methods22,955 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. ResultsBCG 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. ConclusionWe 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)

Novel artful applications of vaccines at the horizon.

Some live vaccines, particularly Bacillus Calmette‐Guérin (BCG), oral polio vaccine (OPV), and measles vaccine, can reduce the incidence of all‐cause mortality by outreaching the mere control of specific infections and exerting off‐target effects. Asides from the prevention of viral infection, some other vaccines, such as those against flu or rotavirus, could reduce the risk of developing autoimmunity. The nonspecific effects of vaccines are mediated by the innate immune system, mainly through the so‐called trained innate immunity. These observations paved the way for developing tolerogenic and trained immunity‐based vaccines with substantial implications for more effective use of vaccines and combat vaccine hesitancy.

Letter to the editor RE: Berendsen etal., 2016 'Non-specific Effects of Vaccines and Stunting: Timing May Be Essential'.

We read with great interest the article by Berendsen et al. [1] In this article, the authors aimed to evaluate the effect of timing of infant vaccination with Bacillus Calmette–Guérin (BCG), DTP1, and measles vaccine (MV) on stunting, among other outcomes. For this purpose, the authors retrospectively used secondary survey data on 368450 children from 33 Sub-Saharan African countries and, using logistic regression analyses, cross-sectionally performed mainly two types of analyses: 1. estimation of the odds of stunting in children with a past BCG, DTP1, and MV vaccination (separately) in comparison to unvaccinated children in overall and stratifying by the timing of vaccination 2.

Evaluation of non-specific effects of human rotavirus vaccination in medical risk infants

BackgroundThe WHO recommends research into non-specific effects of vaccination. For rotavirus vaccines, these have not yet been well established. We studied non-specific effects up to 18 months of age using data from a quasi-experimental before-after study comparing cohorts of rotavirus vaccinated and unvaccinated infants with medical risk conditions. MethodsInfants were enrolled at six weeks of age before and after a stepped-wedge implementation of a hospital-based risk-group rotavirus vaccination program. Other infant vaccinations were administered according to the Dutch National Immunization Program and similar in both cohorts. Non-specific effect outcomes were prospectively collected using monthly questionnaires and included acute hospitalization (excluding for acute gastroenteritis), monthly incidence of acute respiratory illness and eczema. We used time-to-event analysis and negative binomial regression to assess the effect of at least one dose of rotavirus vaccination for each of these outcomes.FindingsThe analysis included 496 rotavirus unvaccinated and 719 vaccinated medical risk infants. In total, 1067 (88%) were premature, 373 (31%) small for gestational age and 201 (17%) had a congenital pathology. The adjusted hazard ratio for first acute hospitalization was 0·91 (95 %CI 0·76;1·16) for rotavirus vaccinated versus unvaccinated infants. Adjusted incidence rate ratio for acute respiratory illness was 1·05 (95 %CI 0·96;1·15) and for eczema 0·89 (95 %CI 0·69;1·15). ConclusionThe results suggest no, or minimal non-specific effects from rotavirus vaccination on acute hospitalization, acute respiratory illness or eczema in medical risk infants.Trial registration: as NTR5361 in the Dutch trial registry, www.trialregister.nl.

Microbial exposures that establish immunoregulation are compatible with targeted hygiene

It is often suggested that hygiene is not compatible with the microbial exposures that are necessary for establishment of the immune system in early life. However, when we analyze the microbial exposures of modern humans in the context of human evolution and history, it becomes evident that whereas children need exposure to the microbiotas of their mothers, other family members, and the natural environment, exposure to the unnatural microbiota of the modern home is less relevant. In addition, any benefits of exposure to the infections of childhood within their household setting are at least partly replaced by the recently revealed nonspecific effects of vaccines. This article shows how targeting hygiene practices at key risk moments and sites can maximize protection against infection while minimizing any impact on essential microbial exposures. Moreover, this targeting must aim to reduce direct exposure of children to cleaning agents because those agents probably exert TH2-adjuvant effects that trigger allergic responses to normally innocuous antigens. Finally, we need to halt the flow of publications in the scientific literature and the media that blame hygiene for the increases in immunoregulatory disorders. Appropriately targeted hygiene behavior is compatible with a healthy lifestyle that promotes exposure to essential microorganisms.

Measles Vaccination in the Presence of Maternal Measles Antibody Reduces All-Cause Child Mortality - A Planned Cohort Study Nested in a Randomised Trial

Background: Several smaller studies suggested that measles vaccination (MV) in the presence of maternal measles antibody (MatAb) reduces all-cause mortality. We tested the hypothesis that children receiving early MV at 4 months in the presence of MatAb would have 35% lower mortality than children receiving MV at 4 months with no detectable MatAb. We further hypothesised that among children, who did not receive early MV, there would be no difference in mortality between those with and without MatAb. Methods: The study was an observational study nested within a randomised controlled trial (RCT) of early MV, carried out in Guinea-Bissau from 2011-2019. The RCT compared the mortality between 4 and 60 months of age for children randomised 2:1 to two doses of MV at 4 and 9 months of age or to only one dose of MV at 9 months of age. At enrolment in the RCT, a blood sample was collected from all children. A multiplex immunoassay was used to determine the measles MatAb level; as control exposures, levels of varicella, mumps and rubella antibody were assessed. We assessed overall mortality as a function of randomisation group and presence of MatAb in Cox proportional hazards models. Results: 6,598 children were enrolled in the RCT, 6,239 (95%) had a valid enrolment blood sample. In children receiving early MV at enrolment, mortality was 50% (95% CI: 20-68%) lower for those vaccinated in the presence of MatAb (n=3132; 51 died) compared with those vaccinated in the presence of no MatAb (n=1028, 31 died). There was no beneficial effect of having MatAb in children who did not receive early MV (test of interaction, p=0.045). The result was specific for measles antibody; no effect was found for varicella, mumps or rubella antibodies. In a meta-analysis of five available studies, MV in the presence of MatAb was consistently associated with lower mortality compared with MV in the absence of MatAb, the combined meta-estimate indicating 55% (35-68%) lower mortality. Interpretation: The results support the previous findings that MV in the presence of maternal antibody enhances the beneficial effects of MV on child survival. Earlier measles vaccination should be considered. Further research is needed to examine whether it is beneficial to vaccinate women of fertile age to transfer higher level of maternal antibodies to their children. Trial Registration (for the RCT): NCT01486355 Funding: The RCT was funded by an ERC Starting Grant to Christine S Benn (ERC-2009-StG-243149) and by a “Center of Excellence” grant from the Danish National Research Foundation (DNRF108). The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3-2011-261375). The funding agencies had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report. Declaration of Interests: Authors declare no competing interests. Ethics Approval Statement: The protocol was approved by the National Ethical Committee in Guinea-Bissau and given consultative approval by the Danish Central Ethical Committee

Systematic review and meta-analysis of the effect of pertussis vaccine in pregnancy on the risk of chorioamnionitis, non-pertussis infectious diseases and other adverse pregnancy outcomes

BackgroundSeveral countries have introduced maternal immunisation with pertussis vaccine to provide protection against pertussis in early infancy. There is increasing interest in non-specific effects of vaccines including that non-live vaccines may enhance susceptibility to non-targeted infections in females. Some studies have shown increased risk of chorioamnionitis among women receiving pertussis vaccine during pregnancy. We aimed to conduct a systematic review and meta-analysis of the effect of maternal pertussis immunisation on the risk of chorioamnionitis, as well as the secondary outcomes of non-pertussis infections in women, non-pertussis infections in infants, spontaneous abortion or stillbirth, maternal death and infant death. MethodsWe searched PubMed and Embase for articles published until January 14, 2021. We screened articles for eligibility and extracted data using Covidence. Quality was assessed using Cochrane RoB tool and Newcastle-Ottawa Scale. Data were imported into RevMan for pooling and conduction of a meta-analysis stratified by study type. Outcomes are presented as risk ratios. ResultsWe identified 13 observational studies and six randomized controlled trials eligible for inclusion. We pooled data on chorioamnionitis from six observational studies and found maternal pertussis vaccine (mostly compared with other maternal immunizations with non-live vaccines) to be associated with an increased risk among the pertussis vaccinated women, RR = 1.27 [CI 95%: 1.14–1.42]. We found no difference in the analysis of our secondary outcomes of non-pertussis infections, spontaneous abortion or stillbirth and death. ConclusionWe found an increased risk of chorioamnionitis among women who received pertussis vaccine in pregnancy. The large number of women receiving pertussis vaccine during pregnancy, as well as the growing evidence of non-live vaccines causing increased susceptibility to infections, indicates a need for further randomised trials to assess potential adverse effects of maternal immunisation with pertussis-containing vaccines.

Stopping Oral Polio Vaccine (OPV) after Defeating Poliomyelitis: A Pyrrhic Victory? Systematic Review of the Non-Specific Effects of OPV

Background: Previous studies revealed that the two live vaccines, BCG and measles vaccine (MV), have beneficial non-specific effects (NSEs) reducing morbidity and mortality more than could be explained by prevention of tuberculosis and measles infection. Since live oral polio vaccine (OPV) is stopped and replaced with inactivated polio vaccine (IPV) in high-income countries and will be stopped globally after polio eradication, we undertook a review of potential NSEs of OPV on mortality. Methods: We searched PubMed for all studies of OPV and death/mortality. In low-income settings, OPV has been provided in three different settings: First, as co-administration of OPV and diphtheria-tetanus-pertussis (DTP) vaccine in three doses from 6 weeks of age. Second, as an early dose at birth (OPV0), often administered together with BCG. Third, in OPV campaigns to eradicate polio infection. We calculated relative risk (RR) of mortality for different combinations of vaccinations and RR of the mortality rate before and after OPV campaigns. Results: The majority of studies was from Guinea-Bissau. First, in three natural experiments, where DTP was missing, OPV-only compared with DTP+OPV co-administered was associated with 3-fold lower mortality rate in two community studies (RR=0.33 (0.14-0.77)) and in a hospital case fatality study (RR=0.29 (0.11-0.77)). Conversely, when OPV was missing, DTP-only was associated with 3-fold higher mortality than co-administration of DTP+OPV (RR=3.23 (1.27-8.21)). Second, in two randomised controlled trials (RCTs), OPV0 vs. no OPV0 was associated with 32% lower infant mortality. The beneficial effects of OPV0 were stronger the earlier the vaccine had been given. Third, in six population-based studies from urban and rural Guinea-Bissau, Burkina Faso and Bangladesh, the mortality rate was lower with a RR=0.75 (0.69-0.82) after OPV campaigns than before OPV campaigns. Furthermore, OPV campaigns changed the mortality effect of health interventions in nine RCTs. The intervention had the strongest beneficial effect before OPV campaigns in all RCTs; hence, OPV campaigns reduced the mortality rate and the difference between randomisation groups disappeared. Interpretation: There have been no polio cases in Guinea-Bissau in this century and no confounding factors or bias would be able to explain these patterns. The only interpretation consistent with all data is that OPV has beneficial NSEs, reducing child mortality. Child mortality may increase again once OPV is removed or replaced with IPV. If no counter-measures are taken, eradicating polio and stopping OPV may become a Pyrrhic victory. Funding: The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3- 2011-261375). CSB held a starting grant from the ERC (ERC-2009-StG-243149). CVIVA was supported by a grant from the Danish National Research Foundation (DNRF108). PA held a research professorship grant from the Novo Nordisk Foundation. Declaration of Interest: Nothing to declare.

Circadian rhythm influences induction of trained immunity by BCG vaccination

BACKGROUNDThe antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity.METHODSEighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age- and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG.RESULTSCompared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning- compared with evening-isolated monocytes.CONCLUSIONSBCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration.FUNDINGThe Netherlands Organization for Scientific Research, the European Research Council, and the Danish National Research Foundation.

The second coming: The comeback of the live vaccines.

Live vaccines are gradually replaced by protein-based vaccines given the latter's better safety. But live vaccines seem to be more efficient via stimulation of the innate immune system.

The non-specific and sex-differential effects of vaccines.

The textbook view of vaccination is that it functions to induce immune memory of the specific pathogen components of the vaccine, leading to a quantitatively and qualitatively better response if the host is exposed to infection with the same pathogen. However, evidence accumulated over the past few decades increasingly suggests that vaccines can also have non-specific effects on unrelated infections and diseases, with important implications for childhood mortality particularly in low-income settings. Furthermore, many of these non-specific effects, as well as the pathogen-specific effects, of vaccines show differences between the sexes. Here, members of the Optimmunize consortium discuss the evidence for and potential mechanisms of non-specific and sex-differential effects of vaccines, as well as their potential policy implications. Given that the non-specific effects of some vaccines are now being tested for their ability to protect against COVID-19, the authors also comment on the broader implications of these trials.

Monocytes from neonates and adults have a similar capacity to adapt their cytokine production after previous exposure to BCG and β-glucan.

The Bacillus Calmette-Guérin (BCG) vaccine is administered at birth in tuberculosis (TB) endemic countries. BCG vaccination is also associated with protective non-specific effects against non-tuberculous infections. This seems at least in part mediated through induction of innate immune memory in myeloid cells, a process termed trained immunity. β-glucan, a component of the fungal cell wall from Candida albicans, induces a trained immunity phenotype in human monocytes with hyper-responsiveness against unrelated pathogens. We aimed to study the capacity of BCG and β-glucan to induce a similar phenotype by examining cytokine production in cord blood monocytes following re-stimulation. We used a well-known model of in vitro induction of trained immunity. Adherent mononuclear cells from neonates and adults, which consist mainly of monocytes, were stimulated in vitro with BCG or β-glucan for one day, after which the stimulus was washed away. Cells were rested for 5 days, then restimulated with LPS. Cytokine levels were measured using ELISA. Neonate and adult monocytes responded similarly in terms of cytokine production. BCG significantly increased IL-6 responses to LPS in both neonate and adult monocytes, while β-glucan induced increases of IL-6, IL-10 and TNF production capacity. The BCG and β-glucan induced increase in cytokine production, reminiscent of trained immunity, showed similar levelsin neonatal and adult monocytes. BCG mediated changes in cytokine production shows the feasibility of this in vitro assay for further studies regarding non-specific effects of vaccines.

Differential effects of BCG vaccine on immune responses induced by vi polysaccharide typhoid fever vaccination: an explorative randomized trial

The Vi polysaccharide typhoid fever vaccine (TFV) provides incomplete protection against typhoid fever. BCG, the vaccine against tuberculosis, can potentiate immune responses to other vaccines through induction of trained innate immunity and heterologous adaptive immunity. We performed an explorative, randomized, noncontrolled open trial to investigate whether BCG vaccination increases humoral and cellular response to TFV and whether BCG and TFV modulate nonspecific immune responses. Thirty volunteers were randomized to receive either TFV alone or BCG followed by TFV after 2 weeks. Ex vivo leukocyte responses and anti-Vi IgG antibody titers were measured 2 weeks and 3 months after TFV. BCG administration prior to TFV vaccination did not increase specific humoral or cellular immune responses to Salmonella typhi. TFV vaccination decreased pro-inflammatory responses to non-related stimuli. This effect was counteracted by prior BCG administration, which also led to decreased IL-10 and increased IL-22 responses to non-related stimuli. In an in vitro model of trained immunity TFV led to immunotolerance, which was partially reversed by BCG-induced trained immunity. BCG does not modulate adaptive immune responses to TFV but partially prevents inhibition of innate immune responses induced by TFV. Nonspecific effects of vaccines to unrelated microbial stimuli must be considered in the evaluation of their biological effects (ClinicalTrials.gov NCT02175420).

National Immunisation Campaigns With Oral Polio Vaccine May Reduce All-Cause Mortality: Analysis of 2004-2019 Demographic Surveillance Data in Rural Bangladesh

Background: West African studies have suggested that national immunisation campaigns with oral polio vaccine (C-OPV) may non-specifically reduce all-cause child mortality rate by 15-25%. We investigated whether C-OPVs had similar non-specific effects in rural Bangladesh from 2004 to 2019. Methods: Chakaria, is a health and demographic surveillance system (HDSS) in Southern Bangladesh. From 2004-2011 the HDSS covered a random sample of households; from 2012-2019 it covered a random sample of villages. Using Cox proportional hazards models, we calculated hazard ratios (HR) comparing mortality for children under 3 years of age after campaigns with OPV-only (C-OPV) versus before C-OPV to assess the “intention-to-treat”-effect of C-OPV. We allowed for different baseline hazard function in the two periods (2004-2011, 2012-2019), with separate models for each period. In the main analysis children were only followed prospectively. Findings: In the main analysis, including 736 deaths (2.0%) among 36,155 children, the HR for after C-OPV was 0.68 (95% confidence interval: 0.51-0.90). No other type of health campaign had similar beneficial results. Each additional dose of C-OPV lowered the mortality rate by 8% (0 to 15%). The number needed to treat (NNT) with C-OPV to save one life between 0-35 months of age was only 109 (100-119) (data not shown). Interpretation: This is the fourth study to show that C-OPV has huge beneficial non-specific effects on child survival. No study has found the opposite. Stopping OPV as planned could have detrimental effects for overall child health in low-income countries. Funding Statement: This research study is funded by core donors who provide unrestricted support to icddr,b for its operations and research. icddr,b is grateful to the Government of Bangladesh, Canada, Sweden and the UK for providing core/unrestricted support. The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3-2011-261375). Declaration of Interests: Nothing to declare. Ethics Approval Statement: Ethical Review Committee of International Centre of Diarrhoeal Disease Research, Bangladesh provided approval for the study.

Out-of-sequence DTP and measles vaccinations and child mortality in Guinea-Bissau: a reanalysis

ObjectivesTo assess whether the sequence of diphtheria-tetanus-pertussis vaccine (DTP) and measles vaccine (MV) was associated with child survival in a dataset previously used to assess non-specific effects of vaccines with...

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

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. 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. 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. 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.

Interacting, Nonspecific, Immunological Effects of Bacille Calmette-Guérin and Tetanus-diphtheria-pertussis Inactivated Polio Vaccinations: An Explorative, Randomized Trial.

Certain vaccines, such as Bacille Calmette-Guérin (BCG), have nonspecific effects, which modulate innate immune responses and lead to protection against mortality from unrelated infections (trained immunity). In contrast, in spite of the disease-specific effects, an enhanced overall mortality has been described after diphtheria-tetanus-pertussis (DTP) vaccination in females. This randomized trial aimed to investigate the nonspecific immunological effects of BCG and DTP-containing vaccines on the immune response to unrelated pathogens. We randomized 75 healthy, female, adult volunteers to receive either BCG, followed by a booster dose of tetanus-diphtheria-pertussis inactivated polio vaccine (Tdap) 3 months later; BCG and Tdap combined; or Tdap followed by BCG 3 months later. Blood was collected before vaccination, as well as at 1 day, 4 days, 2 weeks, and 3 months after the first vaccination(s), plus 2 weeks after the second vaccination. Ex vivo leukocyte responses to unrelated stimuli and pathogens were assessed. Tdap vaccination led to short-term potentiation and long-term repression of monocyte-derived cytokine responses, and short-term as well as long-term repression of T-cell reactivity to unrelated pathogens. BCG led to short-term and long-term potentiation of monocyte-derived cytokine responses. When given together with Tdap or after Tdap, BCG abrogated the immunosuppressive effects of Tdap vaccination. Tdap induces immunotolerance to unrelated antigens, which is partially restored by concurrent or subsequent BCG vaccination. These data indicate that the modulation of heterologous immune responses is induced by vaccination with Tdap and BCG, and more studies are warranted to investigate whether this is involved in the nonspecific effects of vaccines on mortality. NCT02771782.