Scientific research has led to the development of numerous types of vaccines that safely elicit immune responses that protect against infection, and researchers continue to investigate novel vaccine strategies for prevention of existing and emerging infectious diseases. Recent decades have brought major advances in understanding the complex interactions between the microbes that cause disease and their human hosts. These insights, as well as advances in laboratory techniques and technologies, have aided the development of new types of vaccines.
Traditional vaccines consist of entire pathogens that have been killed or weakened so that they cannot cause disease. Such whole-pathogen vaccines can elicit strong protective immune responses. Many of the vaccines in clinical use today fall into this category. However, not every disease-causing microbe can be effectively targeted with a whole-pathogen vaccine.
Scientists first described the ability of inactivated, or killed, microbes to induce immunity in the 19th century. This led to the development of inactivated vaccines, which are produced by killing the pathogen with chemicals, heat or radiation. One contemporary example is Havrix, an inactivated vaccine against hepatitis A virus that was developed by NIAID and partners and licensed in the United States in 1995.
Advances in tissue culture techniques in the 1950s enabled development of live-attenuated vaccines, which contain a version of the living microbe that has been weakened in the laboratory. The measles, mumps and rubella (MMR) vaccine is one example. These vaccines elicit strong immune responses that can confer life-long immunity after only one or two doses. Live-attenuated vaccines are relatively easy to create for certain viruses, but difficult to produce for more complex pathogens like bacteria and parasites.
Modern genetic engineering techniques have enabled creation of chimeric viruses, which contain genetic information from and display biological properties of different parent viruses. A NIAID-developed live-attenuated chimeric vaccine consisting of a dengue virus backbone with Zika virus surface proteins is undergoing early-stage testing in humans.
Instead of the entire pathogen, subunit vaccines include only the components, or antigens, that best stimulate the immune system. Although this design can make vaccines safer and easier to produce, it often requires the incorporation of adjuvants to elicit a strong protective immune response because the antigens alone are not sufficient to induce adequate long-term immunity.
Including only the essential antigens in a vaccine can minimize side effects, as illustrated by the development of a new generation of pertussis (whooping cough) vaccines. The first pertussis vaccines, introduced in the 1940s, comprised inactivated Bordetella pertussis bacteria. Although effective, whole-cell pertussis vaccines frequently caused minor adverse reactions such as fever and swelling at the injection site. This caused many people to avoid the vaccine, and by the 1970s, decreasing vaccination rates had brought about an increase in new infections. Basic research at NIAID and elsewhere, as well as NIAID-supported clinical work, led to the development of acellular (not containing cells) pertussis vaccines that are based on individual, purified B. pertussis components. These vaccines are similarly effective as whole-cell vaccines but much less likely to cause adverse reactions.
Some vaccines to prevent bacterial infections are based on the polysaccharides, or sugars, that form the outer coating of many bacteria. The first licensed vaccine against Haemophilus influenzae type B (Hib), invented at NIH’s National Institute of Child Health and Human Development and further developed by NIAID-supported researchers, was a polysaccharide vaccine. However, its usefulness was limited, as it did not elicit strong immune responses in infants—the age group with the highest incidence of Hib disease. NIH researchers next developed a so-called conjugate vaccine in which the Hib polysaccharide is attached, or “conjugated,” to a protein antigen to offer improved protection. This formulation greatly increased the ability of the immune systems of young children to recognize the polysaccharide and develop immunity. Today, conjugate vaccines are available to protect against Hib, pneumococcal and meningococcal infections.
Other vaccines against bacterial illnesses, such as diphtheria and tetanus vaccines, aim to elicit immune responses against disease-causing proteins, or toxins, secreted by the bacteria. The antigens in these so-called toxoid vaccines are chemically inactivated toxins, known as toxoids.
In the 1970s, advances in laboratory techniques ushered in the era of genetic engineering. A decade later, recombinant DNA technology—which enables DNA from two or more sources to be combined—was harnessed to develop the first recombinant protein vaccine, the hepatitis B vaccine. The vaccine antigen is a hepatitis B virus protein produced by yeast cells into which the genetic code for the viral protein has been inserted.
Vaccines to prevent human papillomavirus (HPV) infection also are based on recombinant protein antigens. In the early 1990s, scientists at NIH’s National Cancer Institute discovered that proteins from the outer shell of HPV can form particles that closely resemble the virus. These virus-like particles (VLPs) prompt an immune response similar to that elicited by the natural virus, but VLPs are non-infectious because they do not contain the genetic material the virus needs to replicate inside cells. NIAID scientists have designed an experimental VLP vaccine to prevent chikungunya that elicited robust immune responses in an early-stage clinical trial.
Scientists at NIAID and other institutions also are developing new strategies to present protein subunit antigens to the immune system. As part of efforts to develop a universal flu vaccine, NIAID scientists designed an experimental vaccine featuring the protein ferritin, which can self-assemble into microscopic pieces called nanoparticles that display a protein antigen. An experimental nanoparticle-based influenza vaccine is being evaluated in an early-stage trial in humans. The nanoparticle-based technology also is being assessed as a platform for development of vaccines against MERS coronavirus, respiratory syncytial virus (RSV) and Epstein Barr virus.
Other relatively recent advances in laboratory techniques, such as the ability to solve atomic structures of proteins, also have contributed to advances in subunit vaccine development. For example, by solving the three-dimensional structure of a protein on the RSV surface bound to an antibody, NIAID scientists identified a key area of the protein that is highly sensitive to neutralizing antibodies. They were then able to modify the RSV protein to stabilize the structural form in which it displays the neutralization-sensitive site.
While most subunit vaccines focus on a particular pathogen, scientists also are developing vaccines that could offer broad protection against various diseases. NIAID investigators in 2017 launched an early-phase clinical trial of a vaccine to prevent mosquito-borne diseases such as malaria, Zika, chikungunya and dengue fever. The experimental vaccine, designed to trigger an immune response to mosquito saliva rather than a specific virus or parasite, contains four recombinant proteins from mosquito salivary glands.
Nucleic Acid Vaccines
Another investigational approach to vaccination involves introducing genetic material encoding the antigen or antigens against which an immune response is sought. The body’s own cells then use this genetic material to produce the antigens. Potential advantages of this approach include the stimulation of broad long-term immune responses, excellent vaccine stability and relative ease of large-scale vaccine manufacture. Many such vaccines are in the research pipeline, although none are currently licensed for human use.
DNA plasmid vaccines comprise a small circular piece of DNA called a plasmid that carries genes encoding proteins from the pathogen of interest. The manufacturing process for DNA plasmid vaccines is well-established, allowing experimental vaccines to be quickly developed to address emerging or re-emerging infectious diseases. NIAID’s Vaccine Research Center has developed candidate DNA vaccines to address several viral disease threats during outbreaks, including SARS coronavirus (SARS-CoV) in 2003, H5N1 avian influenza in 2005, H1N1 pandemic influenza in 2009, and Zika virus in 2016. The time from selection of the viral genes to be included in the vaccine to initiation of clinical studies in humans was shortened from 20 months with SARS-CoV to slightly longer than three months with Zika virus.
Vaccines based on messenger RNA (mRNA), an intermediary between DNA and protein, also are being developed. Recent technological advances have largely overcome issues with the instability of mRNA and the difficulty of delivering it into cells, and some mRNA vaccines have demonstrated encouraging early results. For example, NIAID-supported researchers developed an experimental mRNA vaccine that protected mice and monkeys against Zika virus infection after a single dose.
Rather than delivering DNA or mRNA directly to cells, some vaccines use a harmless virus or bacterium as a vector, or carrier, to introduce genetic material into cells. Several such recombinant vector vaccines are approved to protect animals from infectious diseases, including rabies and distemper. Many of these veterinary vaccines are based on a technology developed by NIAID researchers in the 1980s that uses weakened versions of a poxvirus to deliver the pathogen’s genetic material. Today, NIAID-supported scientists are developing and evaluating recombinant vectored vaccines to protect humans from viruses such as HIV, Zika virus and Ebola virus.