As we will see, many current vaccines offer protection by inducing the formation of neutralizing antibodies. However, that statement contains a hidden tautology; pathogens for which current vaccines are effective may also be pathogens for which antibodies are sufficient for protection. For several major pathogens—malaria, tuberculosis, and HIV—even a robust antibody response is not fully protective. The elimination of these pathogens requires additional effector activities, such as the generation of strong and durable cell-mediated immunity, which are not efficiently generated by current vaccine technologies. These are the issues that face modern vaccine scientists.
16-20 Vaccines can be based on attenuated pathogens or material from killed organisms.
Vaccine development in the early part of the 20th century followed two empirical approaches. The first was the search for attenuated organisms with reduced pathogenicity, which would stimulate protective immunity but not cause disease. This approach continues into the present with the design of genetically attenuated pathogens in which desirable mutations are introduced into the organism by recombinant DNA technologies. This idea is being applied to important pathogens, such as malaria, for which vaccines are currently unavailable, and may be important in the future for designing vaccines for influenza and HIV.
The second approach was the development of vaccines based on killed organisms and, subsequently, on purified components of organisms that would be as effective as live whole organisms. Killed vaccines were desirable because any live vaccine, including vaccinia, can cause lethal systemic infection in immunosuppressed people. Evolving from this approach were vaccines based on the conjugation of purified antigens, as described for Haemophilus influenzae (see Section 16-27). This approach continues with the addition of ‘reverse immunogenetics’ (see Section 16-15) to identify candidate peptide antigens for T cells and with strategies to use ligands that activate TLRs or other innate sensors as adjuvants to enhance responses to simple antigens.
Immunization with such approaches is now considered so safe and so important that most states in the United States require all children to be immunized against several potentially deadly diseases. These include the the viral diseases measles, mumps, and polio, for which live-attenuated vaccines are used, as well as against tetanus (caused by Clostridium tetani), diphtheria (caused by Corynebacterium diphtheriae), and whooping cough (caused by Bordetella pertussis), for which vaccines composed of inactivated toxins or toxoids prepared from the respective bacteria are used. More recently, a vaccine has become available against H. influenzae type b (HiB), one of the causative agents of meningitis, as well as two vaccines for childhood diarrhea caused by rotaviruses, and, as described in Section 16-18, a vaccine for preventing HPV infection for protection against cervical cancer. Most vaccines are given to children within the first year of life. The vaccines against measles, mumps, and rubella (MMR), against chickenpox (varicella), and against influenza, when recommended, are usually given between the ages of 1 and 2 years.
Impressive as these accomplishments are, there are still many diseases for which we lack effective vaccines (Fig. 16.22). For many pathogens, natural infection does not seem to generate protective immunity, and infections become chronic or recurrent. In many infections of this type, such as malaria, tuberculosis, and HIV, antibodies are insufficient to prevent reinfection and to eliminate the pathogen, and cell-mediated immunity instead seems to be more important in limiting the pathogen, but alone is still insufficient to provide full immunity. It is not the absence of an immune response to the pathogen that is the problem, but rather that this response does not clear the pathogen, eliminate pathogenesis, or prevent reinfection.