Abstract
The Keystone Symposia conference, Challenges of Global Vaccine Development, attracted approximately 440 scientists, physicians and students from all around the world. The conference goal was to share newly aquired knowledge regarding vaccine-induced immunity, novel technologies, childhood vaccines, preclinical models, as well as correlates of protection. The different sessions and workshops were divided based on these aspects, even though the focus on involving the developing world in the vaccine development pervaded the meeting. Roughly half of the participants represented academia. As a result of generous scholarships, and the fact that the meeting was held in South Africa, at least 23% of the non-US attendants were of African origin. As the number of oral and poster presentations were too numerous to all be covered in this review, selected highlights will be discussed.
Neonatal & infant immunity
Immunization of newborns represents one of the largest challenges in vaccine development. Effective immunization is complicated by various factors, including the immaturity of the newborn immune system, a general Th2 bias of the immune response, deficiencies in antigen presentation, as well as interference with immunity by passively transferred maternal antibodies. Lorne Babiuk (University of Saskatchewan, Canada) described one approach to link innate and specific immunity in order to enhance vaccine efficacy in neonates by combining host defence peptides, CpG oligonucleotides and polyphosphazenes. The latter compound forms microparticles that are suitable for the delivery of a range of antigens. They are active in both soluble and microspherical form and retain the balance between Th1/Th2 responses by induction of specific cytokines.
The variation in response to vaccines on a population level was highlighted by Myron Levine (University of Maryland School of Medicine, MD, USA). Infants in underprivileged countries commonly demonstrate weaker immune responses to live and inactivated oral vaccines, compared with infants in the industrialized parts of the world. The differences may be due to the presence of intestinal viruses, bacteria or helminths, as well as environmental factors, such as crowding and malnutrition. In order to be able to induce protective immune responses by immunization, it is important to clarify these factors.
Vaccines impacting on microbial ecology
Streptococcus pneumoniae infection is a leading course of childhood mortality and was, until recently, not preventable in young children. The introduction of a pneumococcal conjugate vaccine (PCV) has dramatically reduced the cases of pneumococcal disease in children eligible for vaccination. However, so far, the inclusion of PCV in national immunization programs in developing countries is limited. Shabir Madhi (University of Witwatersrand, South Africa) described two major obstacles that have to be overcome in order to distribute the PCV vaccine worldwide. First, since the current cost of the vaccine is too high for most developing countries, funding has to be made available for the vaccination program in each country. Second, there may be problems with serotype replacement in cohorts vaccinated with pneumococcal vaccines. New serotypes of S. pnemoniae that are not included in the current vaccine may become the dominant circulating strains within a vaccinated population. Madhi proposed that surveillance of serotype replacement and development of new broad-spectrum vaccines may deal with this particular issue.
Tuberculosis
As one of the major threats to public health, tuberculosis (TB) was discussed frequently during the meeting. The current vaccine, Bacille Calmette–Guérin (BCG), is considered outdated and shows limited efficacy, especially against pulmonary TB. A novel vaccine strategy using BCG as a prime, followed by TB-subunit vaccine as a boost, was presented by a number of speakers. This strategy could, potentially, help to increase the TB-specific immune response. An additional challenge for developing new TB vaccines is that the correlates of protection need to be understood. Willem Hanekom (University of Cape Town, South Africa) has addressed this question by analyzing plasma samples from protected and unprotected infants (10 weeks old, South Africa). By studying 11 different cytokines, he concluded that protected individuals had a higher frequency of TB-specific multifunctional T cells. These cells have the capacity to simultaneously secrete a combination of different cytokines (e.g., IFN-γ, IL-2, -12, -13 and -17). This is in contrast to the nonprotected individuals with TB-specific T cells that only produce IFN-γ. Paul-Henri Lambert (University of Geneva, Switzerland) discussed the advantages and disadvantages of Toll-like receptor (TLR) agonists as adjuvants. Activating the innate immunity can help to induce protective T-cell responses but can also induce proinflammatory cytokines. He described the subunit vaccine H1 against TB, which is delivered together with the cationic adjuvant IC31 (Intercell AG, Austria) that signals through the TLR9. This strategy targets peripheral dendritic cells, and limits the adjuvant-related adverse effects. Another speaker to highlight the importance of new vaccines/vaccine strategies to target latent TB was Peter Andersen (Statens Seruminstitut, Denmark). According to Andersen, the current BCG prophylactic vaccination can be optimized using polyprotein fusion molecules (e.g., Ag85B or ESAT6/TB10.4, which consists of subcomponents of TB proteins) as boosts, whereas therapeutic vaccines aiming at survival genes (such as starvation and reactivation genes) can target latent TB. A more recent immunization strategy is based on combining these two strategies, forming a promising vaccine schedule that targets the different stages of TB.
HIV
Britta Wahren (Karolinska Institute, Sweden) described the progress of an ongoing Phase I prophylactic HIV-1 vaccine trial. The multiantigen/multisubtype (subtypes A, B, C and E) vaccine is based on HIV-DNA priming and HIV–recombinant modified vaccinia Ankara (MVA) boosting, which is now evaluated in a Phase I/II trial in Tanzania. This approach has been shown in a previous trial involving Swedish volunteers to induce a broad and strong cellular immune response. Another DNA-prime/MVA-boost vaccine was described by Carolyn Williamson (University of Cape Town, South Africa). Their vaccine constructs are designed to fit the subtype C HIV-1 epidemic in South Africa and the vaccine has proven to induce multifunctional HIV-1-specific CD4+ and CD8+ T cells in nonhuman primates. Gary Nabel (Vaccine Research Center, MD, USA) announced that the scheduled HIV-1 vaccine trial, PAVE 100, may need to be changed in order to be conducted, owing to the discontinued STEP trial performed by Merck. The PAVE 100 trial is a Phase IIB study that planned to include approximately 8500 individuals who will receive DNA priming followed by boosting with recombinant adenovirus 5.
Robin Shattock (St Georges University of London, UK) described his work on intravaginally delivered stable trimeric gp140 (based on the clade C HIV-1 strain, ZM96) vaccine. The vaccine is highly immunogenic and has been shown to induce both mucosal and systemic antibody responses in rabbits. In order to retain the antigen and facilitate a long-lasting exposure to the immune system, the vaccine is currently evaluated in combination with different delivery systems, such as gels, vax-based nanoparticles and intravaginal rings.
Novel vaccine strategies & delivery methods
Novel vaccine strategies, as well as new ways to deliver vaccines were presented. One method of dermal vaccine delivery by targeting the hair follicles was described by Béhazine Combadiére (INSERM, France). By removing the hair and the stratum corneum layer of the skin, the hair follicles can be exposed and targeted with a vaccine. The topically applied transcutaneous vaccine targets dendritic cells and induces systemic CD8+ T-cell responses. However, no neutralizing antibodies were induced against influenza following immunization by this route using inactivated influenza virus.
In the last decade, plant biotechnology has been validated as a promising platform for producing proteins for subunit vaccines, as well as for producing monoclonal antibodies. Several presentations, both during the plenary sessions as well as during workshops, addressed the issue of manufacturing vaccine components in plants. Charles Artzen (Biodesign Institute, Arizona State University, AZ, USA) discussed aspects that make plant technology especially appropriate in meeting production needs in developing countries. Recent technical advancements allow high quantities of recombinant proteins to be produced in a short time. Novel and sophisticated downstream processing has made it possible to produce highly purified protein antigens that may be delivered orally or systemically. Yoshikazu Yuki (University of Tokyo, Japan) presented promising preclinical data on an oral cholera toxin B subunit (CTB) vaccine produced in rice. When fed to mice, the CTB protein was taken up by the microfold cells (M cells) in the gut mucosa and induced mucosal antigen-specific neutralizing immune responses. In addition, TB-recombinant CTB produced in rice has been shown to be stable for at least 1.5 years at room temperature.
Abraham Sonenshein (Tufts University School of Medicine, MA, USA) described a novel method for engineering spore-forming Bacillus subtilis to express vaccine antigens. By delivering B. subtilis expressing tetanus toxid intranasally in mice, it is possible to induce protection against subsequent exposure to the tetanus toxin. Sonenshein plans to combine a variety of antigens from different pathogens to construct a multivalent vaccine delivered mucosally (intranasal or oral).
Rafi Ahmed (Emory School of Medicine, GA, USA) described how programmed death marker-1 is regulated during immune escape in the lymphocytic choriomeningitis virus model. He presented data demonstrating that the blocking of programmed death marker-1 can restore T-cell function and work synergistically with therapeutic immunization in the experimental mouse model. This strategy can, potentially, be utilized for treating chronic viral infections, such as HIV-1, in which the T cells become anergic and dysfunctional during the chronic phase of the infection.
The speaker of the final plenary session, Lennart Hammarström (Karolinska Institute, Sweden), presented a strategy to induce passive immunity using recombinant Lactobacillus paracasei, which has the capacity to colonize the gut. The bacteria are made to express pathogen-specific antibody fragments, either secreted or anchored to the bacterial surface. This model has been shown to partly protect mice against challenge with rotavirus. According to Hammarström, this also constitutes a promising method for passive immunization also against other pathogens.
Conclusion
Despite the tremendous impact that vaccines have had on global health, there is still considerable work to be done, both scientifically and politically. One major task is to make existing vaccines accessible to countries in the developing world. Anna-Lisa Williamson (University of Cape Town, South Africa) concluded that developing countries need to be involved through the whole process of vaccine development, rather than simply being a site for clinical studies and future utilization.
This meeting attracted a wide range of scientists and facilitated interactions between different fields of vaccine research. There is a need to continue to provide opportunities to share data and collaborate on preclinical research, as well as to improve assays used for the read-out of vaccine efficacy, and be able to compare results by employing common models and standardized assays. The correlates of protection against pathogens, such as HIV-1 and TB, remain among the most important problems to solve. Furthermore, since results in animal models and results in man often differ considerably, it is important to test more vaccine candidates in clinical trials. Overall it was a very thorough meeting and an excellent insight into cutting-edge vaccine research.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.