Non-specific immunological effects of selected routine childhood immunisations: systematic review

Abstract

Objective To identify and characterise non-specific immunological effects after routine childhood vaccines against BCG, measles, diphtheria, pertussis, and tetanus.Design Systematic review of randomised controlled trials, cohort studies, and case-control studies.Data sources Embase, PubMed, Cochrane library, and Trip searched between 1947 and January 2014. Publications submitted by a panel of experts in the specialty were also included.Eligibility criteria for selecting studies All human studies reporting non-specific immunological effects after vaccination with standard childhood immunisations. Studies using recombinant vaccines, no vaccine at all, or reporting only vaccine specific outcomes were excluded. The primary aim was to systematically identify, assemble, and review all available studies and data on the possible non-specific or heterologous immunological effects of BCG; measles; mumps, measles, and rubella (MMR); diphtheria; tetanus; and pertussis vaccines.Results The initial search yielded 11 168 references; 77 manuscripts met the inclusion criteria for data analysis. In most included studies (48%) BCG was the vaccine intervention. The final time point of outcome measurement was primarily performed (70%) between one and 12 months after vaccination. There was a high risk of bias in the included studies, with no single study rated low risk across all assessment criteria. A total of 143 different immunological variables were reported, which, in conjunction with differences in measurement units and summary statistics, created a high number of combinations thus precluding any meta-analysis. Studies that compared BCG vaccinated with unvaccinated groups showed a trend towards increased IFN-γ production in vitro in the vaccinated groups. Increases were also observed for IFN-γ measured after BCG vaccination in response to in vitro stimulation with microbial antigens from Candida albicans, tetanus toxoid, Staphylococcus aureas, lipopolysaccharide, and hepatitis B. Cohort studies of measles vaccination showed an increase in lymphoproliferation to microbial antigens from tetanus toxoid and C albicans. Increases in immunogenicity to heterologous antigens were noted after diphtheria-tetanus (herpes simplex virus and polio antibody titres) and diphtheria-tetanus-pertussis (pneumococcus serotype 14 and polio neutralising responses) vaccination.Conclusions The papers reporting non-specific immunological effects had heterogeneous study designs and could not be conventionally meta-analysed, providing a low level of evidence quality. Some studies, such as BCG vaccine studies examining in vitro IFN-γ responses and measles vaccine studies examining lymphoproliferation to microbial antigen stimulation, showed a consistent direction of effect suggestive of non-specific immunological effects. The quality of the evidence, however, does not provide confidence in the nature, magnitude, or timing of non-specific immunological effects after vaccination with BCG, diphtheria, pertussis, tetanus, or measles containing vaccines nor the ...

Non-specific effects of vaccines: plausible and potentially important, but implications uncertain

“…In this systematic analysis of NSIE, undertaken as part of the WHO’s review of NSE, increased production of gamma-interferon after BCG vaccine was the most consistent finding in various in vitro experimental conditions, although some studies showed no effect 33. Overall, the findings, though highly variable, were in line with observations in animal studies that BCG vaccine induces a more proinflammatory state.…”

The immunomodulatory effects of measles‐mumps‐rubella vaccination on persistence of heterologous vaccine responses

“…The precise mechanisms underlying the immunomodulatory effects of live‐vaccines, particularly BCG and MMR, are the subject of ongoing investigations. BCG vaccine, for example, influences the innate and T‐cell immunity by epigenetic reprogramming of immune cells and by altering cytokine responses . Fewer studies have investigated the mechanisms underlying the immunomodulatory effects of MCV.…”

“…9,10,20 The precise mechanisms underlying the immunomodulatory effects of live-vaccines, particularly BCG and MMR, are the subject of ongoing investigations. BCG vaccine, for example, influences the innate [21][22][23] and T-cell immunity 24 Figure 1. Selection of participants.…”

Current challenges and opportunities for bacillus Calmette‐Guérin replacement vaccine candidates

“…Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB) for human in use today. 1 BCG protects against severe extrapulmonary forms of TB in humans (miliary and meningeal forms), [2][3][4][5][6] but offers variable protection against the most common respiratory form of the disease (pulmonary TB) 7,8 and can produce severe adverse effects in immunocompromised individuals. [9][10][11] Therefore, it is contraindicated in HIV-infected individuals.…”