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Vaccines are among the most effective interventions in modern medicine. Ever since Edward Jenner’s first use of a vaccine against smallpox in 1796 (see text box), the use of vaccines has become indispensable to the eradication of disease. In the 20th century alone, smallpox claimed an estimated 375 million lives, but since 1978, after the completion of a successful eradication campaign, not a single person has died from smallpox. Today, more than 70 vaccines have been licensed for use against approximately 30 microbes, sparing countless lives (Fig. 1A and 1B).1,2 Diseases including poliomyelitis, measles, mumps, rubella, and others caused an estimated 39 million infections in the 20th century in the United States, but vaccines have since rendered them uncommon (Table 1).3,4 The success of this public health intervention emanates not only from the identification of effective vaccines but also from a robust infrastructure for vaccine manufacturing, regulatory and safety oversight, and organized approaches to delivery. Vaccines represent the least expensive and most facile way to protect against devastating epidemics. Society derives economic benefits by preventing hospitalization, avoiding long-term disability, and reducing absence from work. In brief, vaccines provide the most cost-effective means to save lives, preserve good health, and maintain a high quality of life.
Despite this legacy, infectious diseases still extract an extraordinary toll on humans. Vaccines have yet to realize their full potential for several reasons. First, effective vaccines are often not available in developing countries. The Global Alliance for Vaccines and Immunization (GAVI) estimates that every year more than 1.5 million children (3 per minute) die from vaccine-preventable diseases. Second, effective vaccines have not yet been developed for diseases such as human immunodeficiency virus (HIV) infection, tuberculosis, and malaria, which claim the lives of more than 4 million people worldwide each year.5–7 For nearly all successful licensed vaccines, natural immunity to infection has been shown, and the vaccine mimics the protective immune response. In contrast, for HIV infection, tuberculosis, and malaria, it has been difficult to show preventive immunity. Protection against these pathogens requires a distinct approach to vaccine design, based on an understanding of immunopathogenesis and reliance on animal models. In these cases, the challenge is greater, the development path longer, and the outcome less certain.
“I have received a copy of the evidence at large respecting the discovery of the vaccine inoculation which you have been pleased to send me, and for which I return you my thanks …. I avail myself of this occasion of rendering you a portion of the tribute of gratitude due to you from the whole human family. Medicine has never before produced any single improvement of such utility. Harvey’s discovery of the circulation of the blood was a beautiful addition to our knowledge of the animal economy, but on a review of the practice of medicine before and since that epoch, I do not see any great amelioration which has been derived from that discovery. You have erased from the calendar of human afflictions one of its greatest. Yours is the comfortable reflection that mankind can never forget that you have lived. Future nations will know by history only that the loathsome small-pox has existed and by you has been extirpated.”
Letter to Dr. Edward Jenner from Thomas Jefferson, Monticello (May 14, 1805)
Finally, many vaccine technologies are old and ill-suited for a rapid response to emerging outbreaks. For example, influenza vaccines rely largely on 50-year-old technology. Current seasonal influenza vaccines are not always well matched and effective against circulating viral strains.8 Furthermore, when new strains emerged unexpectedly from an animal reservoir in the 2009 influenza A (H1N1) pandemic, vaccine developers were unprepared for rapid deployment of a new vaccine strain. Thus, although the triumphs of yesterday’s vaccines have been heartening, a variety of challenges remain for the vaccines of tomorrow. Yet there are reasons to be optimistic that these challenges can be addressed.
Progress in virology, genetics, synthetic biology, and biotechnology has provided a new set of tools to approach current-day vaccinology. Among currently licensed vaccines, the most consistent biomarker for vaccine efficacy has been the presence of antibodies that neutralize the pathogen. These antibodies are often elicited by natural infection or immunization. Our understanding of the molecular structure of viruses has led to a sophisticated understanding of viral glycoproteins and the specific interactions of antibodies that can inactivate them. The field of structural biology has provided new insights into how such antibodies protect against infection by poliomyelitis, measles, and influenza viruses, as well as human papillomavirus (HPV), among others. This detailed knowledge of the mechanism by which viral glycoproteins mediate entry into host cells can now be applied to pathogens that have not been susceptible to this therapeutic approach (Fig. 2).9–11 Thus, an understanding of the steps related to entry and survival of pathogens that cause illnesses such as HIV type 1 (HIV-1) infection, tuberculosis, and malaria offers molecular targets that serve both to understand natural infection and to identify highly conserved and invariant structures as targets for broadly neutralizing antibodies.
The definition of conserved sites of vulnerability on pathogens provides the basis for structure-based vaccine design. Broadly neutralizing antibodies often recognize highly conserved sites that are susceptible to antibody inactivation. Two pathogens, HIV-1 and influenza virus, have proved to be particularly informative in this regard. For example, analysis of the HIV-1 envelope has revealed at least four discrete sites that represent potential targets for the designs of immunogens (i.e., agents capable of inducing an immune response). These include the CD4-binding site, a glycosylated site in variable regions 1 and 2 (V1V2), glycans on the outer domain, and the membrane proximal external region.
Progress in HIV-vaccine research has been advanced recently by the identification of exceptionally broad and potent neutralizing antibodies to each of these sites. Some monoclonal antibodies neutralize more than 90% of circulating viral strains,12–17 creating new opportunities for HIV-vaccine development. Similar progress has been made in the identification of broadly neutralizing antibodies directed against diverse influenza viruses. At least two independent sites of vulnerability have been identified, one in the stem region of the viral spike that helps to stabilize the trimer, the three identical viral hemagglutinin glycoproteins that form this structure, and the other in the receptor-binding region that recognizes sialic acid.18 The existence of such antibodies provides conceptual support and tools that facilitate the development of universal influenza vaccines intended to protect against a wide array of viruses, not only the circulating seasonal strain.
Knowledge of atomic structure also defines viral proteins to elicit these broadly neutralizing antibodies. For HIV infection, alternative forms of envelope glycoproteins include trimers, monomers, subdomains, and specific peptide loops transplanted onto scaffolds.19 These candidate vaccines are further modified with the use of protein-design algorithms that are based on bioinformatics10 in efforts to stabilize the immunogen, better expose the conserved sites, and mask or remove undesired epitopes. Similar strategies are under development for influenza viruses, respiratory syncytial virus, and group B meningococcal strains.9,11,18,20,21
Although structure-based rational design offers a promising tool for developing vaccines against recalcitrant pathogens, substantial challenges remain. The proper antigenic structure will not necessarily provide all the information needed to produce a potent immunogen that will elicit an antibody response. Furthermore, many broadly neutralizing antibodies are atypical, with an unusually high degree of somatic mutation or long CDRH3 (third complementarity determining regions of heavy-chain variable) regions; such antibodies may not be readily elicited. Finally, a successful vaccine candidate must be designed to bind the germline antibody precursor, select for the appropriate primary recombinational events, and direct its somatic mutations toward the appropriate mature form.19
Progress in the field of therapeutic monoclonal antibodies has facilitated the identification of effective targets and led to strategies for their successful use in humans.22 Dozens of new antibodies directed against HIV-1,18,19 influenza virus,21 respiratory syncytial virus,20 hepatitis C virus,18 and other microbes have identified critical viral structures and enabled structure-based vaccine design. Moreover, deep sequencing, the ability to generate millions of independent sequences of a gene product (e.g., immunoglobulin), has identified intermediates that are critical for the evolution of broadly neutralizing antibodies and has guided vaccine development.23 Millions of gene sequences encoding heavy and light chains (the polypeptide subunits of an antibody) within a single individual can be analyzed with the use of bioinformatics to trace a potential critical path for vaccine design (Fig. 3).23 The overarching goal is to use knowledge of structural biology and antibody evolution to design vaccines that will elicit antibodies of known specificity.24
Genomewide sequencing of microbes has also allowed for the rational selection of targets for vaccine development. This approach has identified specific gene products of pathogens as vaccine targets. The expression and evaluation of these immunogens have led to the development of a successful vaccine for group B meningococcal strains through a process known as reverse vaccinology.25
The human immune response has been analyzed with sensitive high-throughput technologies that allow for systems biologic analysis of gene-expression patterns in lymphocytes and in microbes. Such information not only identifies susceptible microbial targets but also has the potential to define new biomarkers of protective immune responses, termed systems vaccinology.26 Mechanisms of protection and correlates of immunity can be rigorously explored in relevant animal models, but these properties can be definitively established in humans only through clinical trials and postlicensure surveillance. Such information enables precise immune activation, minimizes unintended side effects, and maximizes clinical efficacy. Successful protection may require neutralizing antibodies,18 effective T-cell responses,27 or possibly a combination of the two.
Critical to the modulation of the immune response is the presentation of specific antigens to the immune system. Dendritic cells play a central role in this process. Three subgroups of such cells, including two forms of myeloid dendritic cells and one plasmacytoid dendritic cell, each with distinct sets of toll receptors, modulate the response to specific antigens and adjuvants. Traditional vaccines have relied on live-attenuated or inactivated organisms, attenuated bacteria or capsules, or inactivated toxins.28,29 Progress has been made recently in enhancing immunity through a mechanistic understanding of the biology of dendritic cells and their response to adjuvants.30 Alternative delivery, including viruslike particles or structured arrays with the use of phage or nanoparticles, also stimulate effective immunity and provide powerful tools to confer protection for a specific pathogen (Fig. 4).
An increasing number of vaccine vectors have become available to induce potent humoral or cellular immunity. Gene-based delivery of vaccine antigens effectively elicits immune responses by synthesizing proteins within antigen-presenting cells for endogenous presentation on major histocompatibility complex class I and II molecules. DNA-expression vectors, replication-defective viruses, or prime-boost combinations of the two31–35 have proved to be effective in eliciting broadly neutralizing antibodies, especially for influenza viruses.36,37
Prime-boost vaccine regimens that use DNA and viral vectors33 have increased both humoral immunity and memory CD8 T-cell responses.38 For example, a study of a vaccine regimen consisting of a poxvirus vector prime and protein boost (known as the RV144 trial) provided evidence that the vaccine prevented HIV-1 infection among persons in Thailand.39 Eliciting immune responses at portals of infection (e.g., in the respiratory and intestinal epithelial surfaces for pathogens such as influenza virus and rotavirus, respectively) may generate more efficient mucosal immunity. Similarly, waning vaccine responses require periodic boosting at defined times, requiring more integrated management of vaccines at all ages. Immunization in the elderly is of substantial concern because immune senescence can lead to a decrease in the responsiveness to vaccination.40
The effectiveness of vaccines can be tested only in clinical efficacy trials. In the past, advanced clinical development has been undertaken largely by pharmaceutical companies in an effort to obtain licensure. This process is long, costly, and risky with respect to the likelihood of successful protection. For diseases with a major impact on human health but a limited commercial market, there has been little incentive for drug companies to advance these vaccines. For this reason, government involvement can facilitate success. Funding from the Australian government, for example, catalyzed major advances for cholera and HPV vaccines, along with investments from the U.S. National Institutes of Health. Vaccine trials for HIV infection, tuberculosis, and malaria have been facilitated by clinical and translational infrastructure from the National Institute of Allergy and Infectious Diseases, from the European Union, and by nonprofit organizations including the Bill and Melinda Gates Foundation and the Wellcome Trust. Similarly, the Food and Drug Administration (FDA), the European Medicines Agency, the World Health Organization, and the Centers for Disease Control and Prevention (CDC) provide regulatory, safety, and efficacy oversight. The infrastructure for clinical trials is costly but can be applied to studies of multiple infectious agents and can reduce impediments to vaccine development by facilitating logistically challenging trials in the developing world and supporting the collection of serum samples and lymphocytes for further scientific analysis.
New strategies are sometimes needed to facilitate licensure. For infections that are sporadic or intermittent, such as West Nile, Ebola, and Chikungunya viruses, it is often not possible to perform field trials to demonstrate clinical efficacy. To address this problem, the FDA has proposed the animal rule,41 according to which efficacy can be shown in relevant animal species, and immune correlates of protection can be defined. Separate phase 2 studies are then performed in humans with the aim of achieving the same level of immunity, and the bridged immune correlate is used as a criterion for licensure. Although uncertainty would remain about vaccine efficacy in a field setting, this approach allows for the development of vaccines that show a high likelihood of protection but that otherwise would not be developed.
Another impediment has been the inability to identify promising vaccine candidates early in development. Definitive efficacy trials take years to perform, and the ability to advance efficacious vaccines represents a key to success for diverse vaccines, a problem evident in the development of vaccines for HIV infection, tuberculosis, and malaria. A potential solution is to use innovative testing, such as adaptive clinical trial designs.42–44 This approach allows for the evaluation of multiple vaccine candidates in parallel, looking in real time for early efficacy signals to select candidates for more complete and definitive evaluation.45 Innovations in clinical trial design may therefore accelerate early decision making and increase the likelihood of identifying successful vaccines.
The RV144 trial of a candidate HIV vaccine in Thailand showed the value of efficacy testing for identifying efficacy signals and correlates of immunity in humans. Despite the modest vaccine efficacy of 31%,39 investigators found that antibodies to the V1V2 regions of envelope glycoproteins correlated inversely with the risk of infection,46 an unexpected biomarker that may guide product development. Thus, one way to facilitate implementation of successful efficacy trials is to identify promising candidates in phase 1 trials after defining relevant biomarkers through efficacy trials and from relevant vaccine studies in animals, at the same time maintaining stable support and infrastructure for further testing.
Many vaccines are intended for use in the developing world, and the development of clinical infrastructure facilitates the distribution of vaccines in resource-poor settings. Governmental and international vaccination organizations such as GAVI and the United Nations Children’s Fund (UNICEF) help provide commercial vaccines in these settings. Another impediment is vaccine acceptance by the public. For example, resistance to vaccination has been encountered during poliomyelitis eradication campaigns in Nigeria, and unfounded concern related to autism has proved to be counterproductive for vaccine utilization and in protecting public health in the United States. Increased vigilance and a constructive response to these concerns are needed to support public confidence in vaccines and optimize their implementation.47,48 Public–private partnerships can also help to address unmet needs, as exemplified in the development of a meningococcal A vaccine in Africa. Modern vaccine development therefore faces challenges beyond biology, and gaps in implementation must be overcome to realize their full potential.
Advances in immunology and microbiology have opened new avenues to improve vaccine efficacy. New technologies offer alternative products. For example, innovation in manufacturing has allowed a shift from egg-based methods to cell-based or recombinant methods, including production from insect or plant cells. The following examples illustrate other promising developments.
Jenner created the successful smallpox vaccine by building on an observation in nature: milkmaids who were exposed to cowpox were resistant to smallpox. Most licensed vaccines similarly use live-attenuated or inactivated natural pathogens (e.g., influenza, measles, mumps, poliomyelitis, or rubella viruses) to elicit protective immune responses. Yet increasingly, microbes that cause diseases such as HIV infection, tuberculosis, and malaria evade human immunity. To counter immune evasion, subdominant immune responses can be generated to highly conserved invariant regions that are vulnerable to the immune system (Fig. 1). Vaccines of the future will go beyond mimicking natural immune responses and must generate unnatural immunity.9 This goal may be achieved by identifying such targets, validating their susceptibility, and using an expanded arsenal of vaccines to target and expand the otherwise subdominant responses to the core vulnerability of these microbes.
Whereas vaccines are approved for clinical use in the United States by the FDA, standard practices regarding their efficacy, clinical utility, and public health benefit are made by the Advisory Committee on Immunization Practices (ACIP), through the CDC. The ACIP provides advice intended to reduce the incidence of vaccine-preventable diseases and to increase the safety of vaccines, largely in pediatric populations. Yet there are unmet vaccine needs for persons of varying ages, such as the HPV vaccine recommended for adolescents or the shingles vaccine for the elderly. Immune responses also decline with age and vary according to previous pathogen exposure, suggesting that a systematic view of vaccines be adopted for different stages of life,40 a life-cycle management concept for vaccines that can maximize protection at all ages.
While vaccines are under development, the ability of selected antibodies to show protection in humans would validate the antibody target as a protective antigen and provide valuable information about serum levels required for protection. Because techniques with respect to monoclonal antibodies have improved production and bioavailability, such antibodies can be used more broadly for passive prevention. Pilot studies have recently been considered for persons at high risk for HIV infection. If these studies show that such therapy is effective, sustained delivery mechanisms could potentially be achieved with gene-based antibody delivery. Adeno-associated viral vectors have shown efficacy in protecting rodents, nonhuman primates, and humanized mice from lentiviral infection.49,50 However, widespread implementation of this approach is not without its challenges. Notable among them is the need to regulate or extinguish antibody gene expression in the event of unanticipated adverse events, but should this approach succeed with the incorporation of such safeguards, it could fundamentally change strategies of immune protection and speed the delivery and expand the promise of vaccines.
Traditional vaccines have shown unprecedented success in preventing human infectious diseases and preserving public health by alleviating death and suffering from numerous microbial threats. The success of such therapies has heralded the arrival of a new era for vaccines. Increased understanding of human immunity and microbes has catalyzed unprecedented advances that can be adopted to improve public health. Despite continuing challenges, the collective effort of governments and nonprofit organizations to expand the utilization of effective vaccines throughout the world has grown. Scientific, medical, and biotechnologic advances promise to improve the utilization of existing vaccines and expand the horizons for tomorrow’s vaccines.
I thank Drs. Anthony S. Fauci, Harvey Fineberg, Peter Kwong, John Mascola, and Stanley Plotkin for helpful comments and discussions; Dr. Jeffrey Boyington for structural modeling of influenza hemagglutinin; Greg Folkers for advice regarding the composition of the original figures; Ati Tislerics and Mythreyi Shastri for assistance in the preparation of the manuscript; and Brenda Hartman and Jonathan Stuckey for assistance with molecular graphics.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org. Since this article was accepted for publication, the author has moved from the National Institutes of Health to Sanofi