Killed or Live Vaccine, Which One to Choose?

Live, attenuated vaccines and inactivated vaccines are two basic types of vaccines used to protect susceptible individuals from infectious diseases.

Live-attenuated vaccines

Live-attenuated vaccines contain live pathogens, either bacteria or viruses that have been “attenuated,” or weakened. Wild viruses or bacteria are attenuated in a laboratory, usually by repeated culturing. For example, a live attenuated measles vaccine was prepared by almost 10 years of serial passage using tissue culture media.

Live-attenuated vaccines are strong enough to trigger the immune response and produce neutralizing antibodies but too weak to cause disease. If caused disease, it is usually much milder and is considered an adverse reaction to the vaccine.

Benefits of Live Vaccines

The immune response to a live, attenuated vaccine is virtually identical to that produced by a natural infection. In general, live vaccines are preferred to killed vaccines because they offer greater and long-lasting protection.

• When a live vaccine is administered through the natural route of infection, for example, when the polio vaccine is given orally, it multiplies in the intestinal cells of the host and elicits the production of IgA and IgG antibodies. 
• Additional doses, or booster shots, are not always needed with live-attenuated vaccines because the immune system recognizes and remembers live pathogens for a very long period of time.

Although live vaccines stimulate a long-lasting response, booster doses are now recommended with measles and polio vaccines.

Examples of Live Vaccines

• Bacillus Calmette-Guerin (BCG) vaccine contains live attenuated strains of Mycobacterium bovis. It is given to prevent tuberculosis and other mycobacterial infections. BCG vaccine is also used to treat bladder cancer. The vaccine is instilled into the bladder and serves to nonspecifically stimulate cell-mediated immunity, which can inhibit the growth of cancer cells.
• An oral, live attenuated cholera vaccine (Vaxchora) is used to immunize susceptible travelers (age 2 to 64 years) against disease caused by Vibrio cholerae serogroup O1 if they are traveling to cholera-affected areas.
• Influenza vaccine contains temperature-sensitive mutants of influenza virus as the immunogen. This mutant replicates only in the cooler air passage of the ost and induces IgA-based immunity. As it can not replicate in the warmer lung tissue, it fails to cause disease.
• Measles, mumps, and rubella (MMR) vaccine is a live, attenuated vaccine that is effective and long-lasting (at least 10 years) to prevent infection with measles, mumps, and rubella (German measles) virus. Two immunizations are recommended, one at 9-15 months and the booster dose at 4-6 years.
• Live, attenuated polio vaccine, also known as Sabin vaccine or oral polio vaccine (OPV) is used to prevent poliomyelitis. Though both killed/inactivated vaccine and live vaccine are available at present, the inactivated vaccine is preferred because of outbreaks of paralytic polio caused by vaccine-derived poliovirus (VDPV).
• Live, attenuated vaccine against rotavirus (Rotarix) contains the single most common rotavirus serotype (G1) and is given to children (exception children with a history of intussusception) to protect from rotavirus infection.
• Varicella vaccine (Varivax) and zoster vaccine (Zostavax) contain live, attenuated varicella zoster virus. They are used to prevent varicella and zoster respectively. Zostavax contains 14 times more virus than Varivax. The varicella vaccine is recommended for children of 1-12 years, whereas the zoster vaccines are recommended for people older than 50 years.

Limitations of Live Vaccines

1. Attenuated strains of pathogens may revert to virulent form either during the production of vaccines or in the immunized person. Of the commonly used live vaccines, only a polio vaccine has had problems regarding reversion to wild forms. Such reversions have not yet been seen with measles, mumps, rubella, and varicella vaccines.
2. Live vaccine should not be given to immunocompromised people or to pregnant women because although attenuated (weakened), it can still be pathogenic in hosts with weakened immunity. Live, attenuated vaccine may cause severe or fatal infections in persons with a weakened immune system (people suffering from leukemia, HIV infection, or ongoing treatment with certain drugs).
3. Vaccinated individuals excrete live vaccines in the environment. It is a double-edged sword. For example, the spread of the live attenuated poliovirus vaccine through the feces of the immunized individuals can successfully immunize other persons in that particular locality thus aiding in the production of herd immunity but if the virus reverts to wild type, the neurovirulent strain may spread to susceptible person and may cause paralytic polio (a rare event though).
4. Contamination of the candidate vaccine by another virus during production may create problems.
5. Live, attenuated vaccines must be stored and handled carefully as they are fragile and can be damaged or destroyed by heat and light.
6. Circulating antibodies if present in the host (antibodies transferred from mother to child or antibodies due to previous sub-clinical infections or got via transfusion of blood products) can interfere with the replication of the vaccine organism and lead to poor response or no response to the vaccine, also known as vaccine failure.

Note: People who are allergic to eggs (who have shown anaphylactic reactions to eggs) should not get vaccines grown in chick embryos. For example, influenza, measles, mumps, and yellow fever vaccines.

Inactivated (killed) vaccines

Inactivated or killed vaccines contain “wild viruses or bacteria that have been killed or inactivated with heat or chemicals. Viral vaccines are inactivated with either formaldehyde or beta-propiolactone (BPL). Formaldehyde is used for the inactivation of poliovirus, hepatitis A virus, Japanese encephalitis virus, and tick-borne encephalitis virus whereas BPL is used for the inactivation of Rabies and Influenza virus vaccines.

Inactivated vaccines include whole-cell inactivated vaccines (such as polio, hepatitis A, and rabies vaccine), subunit vaccines (e.g., influenza pneumococcal vaccines), toxoids (e.g., diphtheria and tetanus toxoid), and recombinant vaccines (e.g., hepatitis B, human papillomavirus (HPV) and influenza). Killed vaccines are usually given intramuscularly and multiple doses are required to produce protective immunity. Inactivated vaccines mostly provide humoral immunity with little or no cell-mediated immunity.

Benefits of Killed Vaccine

• Inactivated vaccines are safe for immunocompromised people as they cannot revert to virulence. Killed vaccine can be used to immunize pregnant women.

• Killed vaccines are more heat-stable so are easy to handle (storage and transport won’t be the problem, compared with live vaccines).

Limitations of Killed Vaccine

• Inactivated vaccines are weaker than natural infection or live vaccines, so they often require multiple shots in order to build immunity and offer full protection. For example, killed vaccines against the influenza virus must be given annually as it is not a good immunogen.
• The killed vaccine is not a good immunogen, it only stimulates the production of only IgG (not IgA and IgG both), that too with low titer. Killed vaccines also do not stimulate a cytotoxic-T-cell response.
• Antibody titers against inactivated vaccines diminish with time. As a result, some inactivated vaccines may require periodic supplemental doses to increase or “boost” antibody titers.

Examples of Killed Vaccines

1. Killed Vibrio cholerae vaccine is used in many cholera endemic countries.
2. Killed polio vaccine also known as IPV or Salk vaccine is the preferred vaccine to prevent poliomyelitis. It contains all three serotypes of the virus responsible for causing poliomyelitis. The current version of the inactivated vaccine is called enhanced polio vaccine, or eIPV. eIPV has a higher seroconversion rate and induces a higher titer of antibody compared to previous IPV.
3. Killed Yersinia pestis vaccine is indicated for persons at high risk for contracting plague.
4. Vaccine against typhus contains killed Rickettsia rickettsiae and is used primarily to immunize members of the armed forces.
5. The vaccine against Q fever contains killed Coxiella burnetii . It is used to immunize those who are at high risk of being exposed to animals infected with the organism.

Difference Between Live and Killed Vaccines

References and further readings

• Understanding Six Types of Vaccine Technologies. pfizer.com 25 April 2022.
• Authors. Levinson W, & Chin-Hong P, & Joyce E.A., & Nussbaum J, & Schwartz B(Eds.), (2020). Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 16e. McGraw Hill. 
• US Food and Drug Administration.
• Sanders, B., Koldijk, M., & Schuitemaker, H. (2014). Inactivated Viral Vaccines. Vaccine Analysis: Strategies, Principles, and Control, 45–80. https://doi.org/10.1007/978-3-662-45024-6_2