Vaccine Modalities – Part 1

by Gertrud U. Rey

During the last 50 years, vaccination efforts have prevented about 154 million deaths worldwide, with the measles vaccine alone responsible for a large portion of this achievement. Childhood vaccinations in particular have not only led to a 40% reduction in global infant deaths throughout the same time period, but they are also considered one of the most impactful and cost-effective health interventions in the history of biomedical science.

The first successful vaccine was developed in 1796 by the English physician Edward Jenner. Jenner noticed that milkmaids who had been infected with cowpox virus were immune to smallpox, a highly contagious and deadly disease caused by the related variola virus. To see whether cowpox virus could prevent smallpox disease, he inoculated an 8-year-old boy by transferring pus from a milkmaid’s cowpox blister into scratches made on the boy’s arms. Two months later, he injected the boy with material taken from a patient with smallpox, and the boy never developed smallpox, suggesting that Jenner’s hypothesis was correct. Current smallpox vaccines are made from a relative of variola virus called vaccinia virus, which is a more stable and safer alternative to cowpox virus, with a reduced risk of serious side effects. Nevertheless, Jenner’s method of using cowpox virus to prevent smallpox laid the foundation for modern immunization and led to the term “vaccine,” which is derived from “vacca,” the Latin word for “cow.”

Both Jenner’s and modern smallpox vaccines are attenuated vaccines, which are typically produced by serially passaging a pathogen through tissue culture, embryonated eggs, or live animals. Pathogens in attenuated vaccines are only capable of minimal replication, which stimulates the immune system to produce antibodies and T cells against the immunizing pathogen. Smallpox vaccines are attenuated virus vaccines that contain a replication-competent virus (vaccinia virus) that is related to the smallpox-causing virus (variola virus), but is much less harmful. Other attenuated vaccines include the measles, mumps, and rubella (MMR) vaccine, yellow fever vaccine, varicella (chickenpox) vaccine, rotavirus vaccine, and the oral polio vaccine (OPV), which is used primarily in underdeveloped countries. Although attenuated vaccines can be very effective for preventing the disease caused by some pathogens, they may not be safe for use in immunocompromised individuals. In addition, their capacity for replication may sometimes bring about mutations that lead to a more virulent, disease-causing form. This phenomenon, which is a particular problem with the OPV vaccine, was discussed in detail in a previous post.

In contrast to attenuated vaccines, inactivated vaccines contain pathogens that cannot replicate because they have been rendered inactive by physical or chemical means. Although the pathogen itself is not viable, the immune system recognizes antigens on the pathogen as foreign, and mounts a cascade of defenses that protect from later infection and disease induced by that pathogen. It is critical to understand that because these vaccines are not infectious, they are incapable of causing the disease induced by the pathogen. Examples of inactivated vaccines include the inactivated polio vaccine (IPV – used in most developed countries), the hepatitis A vaccine, the rabies vaccine, and most influenza vaccines.

Toxoid vaccines are made from inactivated toxins produced by bacteria. Upon injection, the recipient’s immune cells recognize these toxins as foreign and produce protective responses against the bacteria. The most common example of this type of vaccine is the Tdap (tetanus, diphtheria & acellular pertussis) vaccine, which protects against Clostridium tetani, Corynebacterium diphtheriae, and Bordetella pertussis; the bacteria that cause tetanus, diphtheria, and pertussis, also known as the whooping cough.

Subunit vaccines consist of the purified antigenic parts of a pathogen. Because these vaccines don’t contain the whole pathogen, they are extremely safe. Examples of subunit vaccines include the respiratory syncytial virus (RSV) vaccine, the human papillomavirus (HPV) vaccines, and the hepatitis B vaccine. The RSV vaccine, which was previously discussed here, consists of a stabilized form of the highly conserved RSV F protein. This vaccine exemplifies a phenomenal scientific breakthrough, achieved after many decades of significant research challenges. HPV vaccines consist of hollow virus-like particles lacking viral DNA and are composed of recombinant inactivated L1, the main structural capsid protein of HPV. All HPV vaccines, which were previously discussed here, stimulate production of antibodies that neutralize various pathogenic HPV strains, thus preventing infection with those strains. The hepatitis B and HPV vaccines are notable for not only preventing disease, but also preventing specific types of cancer associated with those diseases. The hepatitis B vaccine prevents liver cancer, and the HPV vaccine has led to a remarkable reduction in cervical cancer, with a potential to eradicate it altogether.

Conjugate vaccines are a type of subunit vaccine that combines a strong antigen with an antigen of interest that has weak immunogenicity, so that the immune system can recognize and respond to the weak antigen. Some bacteria have outer coats that are poorly immunogenic, and it is thus difficult to produce effective vaccines against them. By linking these outer coat antigen domains to highly immunogenic proteins, the immune system can be led to recognize, and react to, the poorly immunogenic bacterial coat. Examples of conjugate vaccines include the pneumococcal conjugate vaccine (PCV), the meningococcal conjugate vaccine (MCV), and the Haemophilus influenzae type B (Hib) vaccine. Each of these vaccines can prevent pneumonia, meningitis, and bacteremia.

Vaccine research has led to so many different vaccine delivery systems that it would be overwhelming to cover them all in one post. I will describe more recent advances in vaccine technology in my next post. Stay tuned!