Biological challenges to effective vaccines in the developing world

Maternal exposure to infection and the infant response to BCG and other vaccines

Professor Alison Elliott, MRC/UVRI, Uganda and London School of Hygiene and Tropical Medicine, UK

Abstract

Maternal infections and their treatment may influence the development of the foetal immune response, and the neonatal and the infant response to exposures including immunisation and infection, in important ways. Maternal antibodies may provide passive “protection” against the homologous infection (or vaccine organism), or may be involved in trans-placental transfer of antigen and pre-natal exposure of the foetus to relevant antigens. Such pre-natal exposure may result in sensitisation, promoting protective responses, or tolerisation, perhaps dependent upon the stage of foetal development at which the exposure occurs. The profile of immune response induced following exposure to vaccine-related antigens in utero may be influenced by co-exposure to antigens from pathogens, such as helminths, that induce a particular bias in the immune response, or by non-specific effects of maternal infections upon the innate immune response. These effects may be important in determining the efficacy of immunisation programmes in disease-endemic settings.

Malnutrition and response to vaccines

Dr Andrew Prendergast, Queen Mary University of London, UK and Zvitambo Institute for Maternal and Child Health Research, Zimbabwe

Abstract

Malnutrition underlies 45% of deaths among children under 5 years, and is the most common immunodeficiency globally. However, relatively little is known about the immunology of malnutrition. Most data are from cross-sectional studies of hospitalised children with severe malnutrition, a high burden of co-infections and micronutrient deficiencies, and establishing the relative contribution of each is challenging. Immune function in children with mild-moderate malnutrition, which accounts for the global burden of undernutrition, is poorly characterised. Severe malnutrition is associated with profound derangements in physiology, reduced epithelial barrier function, enteropathy and impaired innate and adaptive immune function. Children with severe malnutrition (particularly oedematous malnutrition) have reduced rates of seroconversion and lower antibody titres in response to injectable vaccines, whereas children with mild-moderate malnutrition generally appear to have normal vaccine responses. Oral vaccines have lower immunogenicity among children in developing compared to developed countries, which may be due to the overlapping and interacting causes of enteropathy that are almost universal in conditions of poverty. More longitudinal studies of children with mild-moderate malnutrition, using contemporary immunological techniques, are required to better characterise how stunting, low birth weight, suboptimal breastfeeding and moderate acute malnutrition are associated with an elevated risk of infectious morbidity and mortality, and whether vaccine responses are impaired in these children.

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Responses to pneumococcal vaccines in the context of HIV infection

Professor David Goldblatt, University College London Institute of Child Health, UK

Abstract

Streptococcus pneumoniae is the leading bacterial opportunistic infection in HIV-infected individuals. Anti-retroviral treatment (ART) of HIV-infected individuals reduces their risk of invasive pneumococcal disease (IPD), however susceptibility remains 20- to 40-fold higher compared to age-matched general population. The increased susceptibility of HIV-infected individuals to pneumococcal infection relates to likely impairment of both cell-mediated and humoral arms of the immune system. Pneumococcal polysaccharide capsules are the target for protective antibody. In healthy individuals an immunologic response to pneumococcal polysaccharides, a T-cell independent type antigen, elicits production of serotype-specific opsonic antibodies by B lymphocytes independent of T-lymphocyte interaction. In HIV this response is impaired and consequently the use of a vaccine derived from pure pneumococcal polysaccharides (Pneumovax 23) was not associated with efficacy in a trial in HIV infected adults in Africa. New generation pneumococcal vaccines consist of a carrier protein chemically conjugated to the capsular polysaccharide of Streptococcus pneumoniae which transform the immune response to the polysaccharide from T independent to T dependent with profound implications for those with impaired immune responses to pure polysaccharide (eg the young). Pneumococcal conjugate vaccines (PCVs) have proven to be highly efficacious in infants when introduced into routine infant immunisation. In addition a 7 valent PCV has been shown to be efficacious in HIV infected adults and children in Africa. Experience to date with PCVs will be reviewed.

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Immune tolerance induction by breastfeeding

Dr Valérie Verhasselt, University of Nice Sophia-Antipolis, France

Abstract

Early life is characterised by a high susceptibility to infectious diseases due to poorly efficient immune responses against pathogens. This highlights the importance of maternal help for immune defence by continuous transfer of antibodies after delivery through breast milk. Early life is also characterised by higher susceptibility to allergic disease which reveals an impaired capacity to generate regulatory immune responses towards innocuous dietary and environmental antigens. We have been studying in a mouse model how maternal milk can influence the process of immune tolerance establishment. We have demonstrated that both dietary but also respiratory antigen can be transferred orally to the neonate through breast milk.  We have identified that some key antigens specificities, maternal milk co-factors, and neonate characteristics such as their age, micronutrient level and DC function, are determinant for efficient long term tolerance induction versus effector immune responses development. The identification of such mechanisms should help to improve strategies of prevention of both allergic and infectious disease.

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Do probiotics and antibiotics improve antibody responses to oral vaccines and natural infection?

Professor Gagandeep Kang, Christian Medical College, Vellore, India

Abstract

Supplementation with specific strains of probiotics have been shown to have modulatory effects on innate and acquired immunity in animal models and human studies. In human studies with natural infection and vaccines, results have varied by age, antigen, type of antibody response and probiotic strain. A clinical trial of supplementation with Lactobacillus rhamnosus GG in Indian children acutely infected with rotavirus demonstrated significantly greater increase in IgG in supplemented children. A further trial with the same probiotic given before, during and after oral rotavirus vaccination with and without zinc demonstrated an increase in IgA responses. Recent studies in mice have demonstrated a role for the host microbiota in determining immune response to inactivated vaccines, indicating that antibiotics may play a role in response to some vaccines, lending support to the rationale for an ongoing study on response to oral polio vaccination in Indian children.

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Genomics of immune response to typhoid and cholera vaccines

Professor Partha Majumder, National Institute of Biomedical Genomics, India

Abstract

To assess the role of genomic factors associated with immunological response to typhoid and cholera vaccines, we have conducted two large studies in India. Typhoid: Significant associations of response with SNPs in 7 genes (DEFB1, TLR1, IL1RL1, CTLA4, MAPK8, CD86, IL17D) were discovered and cross-validated. These genes are involved in polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signalling and eventual production of antimicrobial peptides. Cholera: Significant associations of SNPs and haplotypes in three genes (MARCO, TNFAIP3, CXCL12) with response were discovered and validated. LPS, present in the vaccine, is a potent activator of innate immune responses and a ligand of MARCO. CXCL12 is a neutrophil and lymphocyte chemoattractant that is upregulated in response to V. cholerae infection. LPS in the vaccine possibly provides signals that mimic those of the live bacterium. TNFAIP3 promotes intestinal epithelial barrier integrity and provides tight junction protein regulation; possible requirements for adequate vaccine-response.

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All-trans retinoid acid as an oral adjuvant

Professor Paul Kelly, University of Zambia School of Medicine, Zambia and Queen Mary University of London, UK

Abstract

There is a pressing need for effective oral vaccines against intestinal infectious diseases. Not only is there a shortage of such vaccines – only three licensed vaccines are available – but there is strong evidence that rotavirus vaccine is less effective in the developing world. We have published data from human volunteer studies in Africa which appear to show that IgA specific to typhoid vaccine in gut secretions can be augmented using all-trans retinoic acid (ATRA). We now show that this is not dependent on vitamin A status. In contrast to animal studies, ATRA does not appear to increase expression of gut homing receptors in humans, except when given simultaneously with typhoid vaccine in which context cooperative responses on CD4 cells are seen with parallel changes in α4β7 and CCR9. Ongoing studies aim to clarify the implications of these responses for responses to typhoid and other oral vaccines.

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Environmental enteropathy, coinfection and oral vaccine response

Professor William Petri, University of Virginia, USA

Abstract

Environmental enteropathy (EE) is a poorly defined state of intestinal inflammation without overt diarrhea that occurs in individuals exposed over time to poor sanitation and hygiene. It is characterised pathologically by small intestine villous blunting and inflammation. We sought to test non-invasive biomarkers for their ability to measure EE.  700 children from an urban slum in Dhaka, Bangladesh were enrolled in the first week after birth and followed until one year of age. Children received twice-weekly household visits, diarrhea surveillance, and serial laboratory studies through18 weeks. We discovered that enteric infection was universal, with an average of two enteropathogens per child at 6 and 10 weeks of age. Nonpolio-enterovirus infection at the time of vaccination was associated with OPV failure. OPV failure and malnutrition at one year were predicted by biomarkers of systemic inflammation and intestinal injury and inflammation. We concluded that biomarkers of EE identify children at risk for OPV failure and malnutrition, and may offer a means to risk-stratify children for early intervention.

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Genes and vaccine responses

Professor Andrew Pollard, University of Oxford, UK

Abstract

Genetic factors have been established in twin studies as directing the immune response to vaccines in early childhood and both candidate gene and genome wide association studies have been used to identify some of the major players in the control of such responses. Despite important insights the picture remains incomplete but studies of extreme phenotypes, including vaccine failures, can provide important new information. Recent studies have used analysis of post-immunisation gene expression in combination with detailed immunophenotyping to identify signatures of transcription that are correlated with antibody and cellular responses providing entirely new lines of investigation and the potential for development of new approaches to vaccination that enhance the relevant pathway for optimal responses.

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Systems-based approaches to vaccine development

Professor Bali Pulendran, Emory University, USA

Abstract

Despite their great success, we understand little about how effective vaccines stimulate protective immune responses. Two recent developments promise to yield such understanding: the appreciation of the crucial role of the innate immune system in sensing microorganisms and tuning immune responses, and advances in systems biology. In this presentation, I will discuss how these developments are yielding insights into the mechanism of some of the most successful vaccines ever developed. Furthermore, such developments promise to address a major challenge in vaccinology: that the efficacy of a vaccine can only be ascertained retrospectively, upon infection. The identification of molecular signatures induced rapidly after vaccination, which correlate with and predict the later development of protective immune responses, would represent a strategy to prospectively determine vaccine efficacy. Such a strategy would be particularly useful when evaluating the efficacy or immunogenicity of untested vaccines, or in identifying individuals with sub-optimal responses amongst high risk populations, such as infants or the elderly. We have recently used a systems biology approach to identify early gene signatures that correlate with, and predict the later immune responses in humans vaccinated with the live attenuated yellow fever vaccine YF-17D, or with the influenza vaccines. I will review these studies, and discuss their broader implications for vaccinology.

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Innate immunity and vaccine responses in African infants

Professor Beate Kampmann, Imperial College London, UK and MRC Unit The Gambia

Abstract

Growing observational evidence shows that immune responses to infection and vaccination might differ between continents and populations. In order to gain mechanistic insights into underlying pathways, we and others have performed stimulation experiments using toll-like receptor agonists and/or vaccine antigens/whole organism, e.g. BCG. The results highlight age-dependent differences in innate and acquired immune responses, but also the impact of maternal antibody and maternal T-cell mediated immune responses to HIV and mycobacteria on innate immune cells. My presentation will summarise recent results from our own work in the UK and Africa and place them in the context of published studies from other investigators in this field.

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Follicular helper T cells and immune memory

Professor Shane Crotty, La Jolla Institute for Allergy & Immunology, USA

Abstract

T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of B cell memory. The development of virtually all neutralizing antibodies is CD4 T cell dependent. Tfh cells are the unique and specialized T cells for B cell help, required for development of germinal centers, affinity matured Abs, and most B cell memory. T cell help is frequently a primary limiting factor for these processes. Therefore understanding and controlling Tfh cells is important for developing true rational vaccine development strategies (Crotty, ARI 2011). Tfh cells are also potentially extremely useful biomarkers in human vaccine clinical trials. Tfh depend on expression of the transcription factor Bcl6, and there are multiple steps required for follicular helper T cell differentiation. We identified circulating memory CXCR5⁺ PD-1^lo  CD4⁺ T cells in normal individuals that are resting memory cells most related to bona fide GC Tfh cells. Importantly, the frequency of these cells correlated with development of broadly neutralizing antibodies against HIV in a large cohort of HIV+ individuals. I will discuss the relevance of Tfh for human vaccine development.

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Developing vaccines against enteric infections in developing countries

Professor Cecil Czerkinsky, Institut de Pharmacologie Moleculaire et Cellulaire, CNRS-INSERM-University of Sophia-Antipolis, France

Abstract

As of today, all vaccines but one (oral polio vaccine) recommended by the Expanded Program on Immunization are administered by way of injections. As such, these vaccines induce immunity in blood and in peripheral tissues but are relatively inefficient for eliciting immune responses in mucosal tissues such as the gastrointestinal tract, the target of enteric infections. On the other hand, mucosal (oral, sublingual, nasal, rectal) administration of a number of experimental as well as few licensed enteric vaccines have been shown to be more efficient for inducing mucosal intestinal immune responses in animals and in humans. Modern biotechnology has yielded an abundance of mucosal vaccine candidates against enteric infections but only few vaccines have been registered for human use, albeit in certain age groups. Extensive efforts are being deployed to design new and safe adjuvants for mucosal immunisation, to identify alternative delivery routes, and to develop new vectors and carrier/delivery systems for tissue- and cell-specific targeting of vaccines. If these candidates are to ultimately reach those in need in developing countries, several lessons from clinical and field research done in these settings must be considered. These lessons include the need to develop vaccines that avoid the need for storage in a cold chain and that can be administered without needles or expensive delivery devices. These vaccines must be safe and work in the world’s poorest, including undernourished children, and must be able to contain epidemics following complex emergencies. Finally, an ideal mucosal vaccine should confer long-term protection and especially herd immunity.

Knowable unknowns along the path to effective vaccines for HIV, malaria and other global health challenges

Dr Chris Wilson, Bill & Melinda Gates Foundation, USA

Abstract

Animal models can help to elucidate the principles of host pathogen interactions and to gain initial insights regarding the immunogenicity, safety and possible protective efficacy of vaccines. However, their predictive power is limited and few are truly fit for purpose. Hence, there is no substitute for human trials for testing new vaccine concepts and making decisions about whether vaccine concepts and candidates should advance. Historically, human testing of new vaccine concepts has been largely limited to just those decisions, with little attention to understanding the causal mechanisms for failure or partial but insufficient efficacy. Done in the name of reducing costs, such approaches lead to excessive costs and delays when addressing the most intractable of diseases, such as HIV, TB and malaria for which vaccines have to be more effective than naturally acquired immunity and the probability of success for candidates is low. New systems approaches and more nimble human exploratory test of concept trials provide the opportunity to better illuminate these causal mechanisms at an early stage and to thereby foster a more rapid, iterative cycle of vaccine improvement before embarking upon large, late stage clinical trials with suboptimal candidates.

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Getting new vaccines to people who need them

Dr Rino Rappuoli, Novartis Vaccines, Italy

Abstract

Thanks to the Global Alliance for Vaccines and Immunisation (GAVI), the Vaccine Fund, and the Bill and Melinda Gates Foundation, we have made enormous progress in providing already existing vaccines to developing countries. However, we are still struggling to develop those vaccines for which there is no market in the western world, because there is no incentive for the private sector to justify the investments necessary for vaccine development.  In many cases we have the technologies, but not the resources to develop these vaccines.  The present emergency with the Ebola vaccine provides an excellent example where a vaccine was feasible several years ago, but we waited for a humanitarian disaster to rush a vaccine into development.

Several institutions dedicated to the development of vaccines against diseases present only in low-income countries emerged during the last few years. These include the International Vaccine Institute, Korea, the Novartis Vaccines Institute for Global Health, Italy, the Hillemann Institute, India, the Sabin Vaccine Institute, and the Infectious Disease Research Institute, USA. Nevertheless, solving this problem requires a much more significant global effort than what we have now, including a clear policy, global coordination of funds dedicated to development of orphan vaccines, agreement on regulatory strategies and incentives for the private sector.

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