Vaccines Part 2 Reading Parham pages 308 325

Vaccines Part 2 Reading: Parham pages 308 -325 Image from John M. Barry, “The Great Influenza” describing the influenza pandemic that killed at least 20 -30 million people worldwide in 1918 -1919

Learning Objectives for Vaccine lecture II part I • Define herd immunity and explain the importance of vaccination campaigns to maintain herd immunity • Explain how the smallpox vaccine was originally created and why the smallpox and polio viruses were good candidates for global eradication through vaccination • Define attenuation and describe different methods to produce attenuated pathogens • Compare and contrast the benefits of attenuated (live) versus killed vaccines using the Sabin and Salk vaccines as an example • Describe vaccines used for the influenza virus, and why new influenza vaccines are required every year

Learning Objectives for Vaccine lecture II part II • Compare contrast the nature and usefulness of the different types of vaccines discussed: Attenuated, Inactivated, Subunit, Conjugate and genetically engineered; provide examples for each type of vaccine. • Compare and contrast the terms exotoxin, toxoid, antitoxin and endotoxin • Describe the advantage that subunit vaccines provide, using the HBV and DPa. T vaccines as examples • Describe the importance and usefulness of conjugate vaccines for capsular bacteria, such as H. influenza and S. pneumoniae • Compare and contrast the two available rotavirus vaccines • Describe the function of adjuvants in vaccines

Effectiveness of vaccination for some common infectious diseases Abbas Fig. 1 -2

Vaccines induce artificial active immunity. In contrast, antiserum (antibodies) is example of artificial passive immunity. FYI, I won’t ask about scheduling of vaccines in PBS 803 Parham Fig. 11. 15

Herd immunity high proportion of individuals with immunity protect the vulnerable members of population Image by NIAID is licensed under https: //creativecommons. org/licenses/by/2. 0/

Herd immunity thresholds for common childhood diseases inadequate immunization rates threaten herd immunity

Decline in measles incidence after approval of measles vaccine in USA

Misinformation about the risks of vaccines has led to increase in disease as herd immunity is lost False claims were made of link between mercury in MMR and autism Evidence shows no link between MMR vaccine and autism Parham Fig. 11. 24

Shared antigenic determinants between cowpox virus and smallpox viruses led to first modern vaccine Edward Jenner-produced first modern vaccine by injecting cowpox into patients in 1796 to protect against smallpox

Vaccination Strategies Inactivated (killed) virus represents another type of virus (Salk vaccine for Polio) Abbas Fig. 8. 15

Killed or inactivated viral vaccines Examples: Salk vaccine (IPV) and the TIV vaccine for Influenza virus (IPV = Inactivated Polio Vaccine) (TIV = Trivalent Inactivated Vaccine) The Salk vaccine was created by inactivating the 3 polio strains with formalin. Formalin denatures viral proteins to make them inactive. If too much formalin used, vaccine not effective, if too little formalin used, vaccine could contain live virus. TIV created by growing three emerging influenza strains in eggs, inactivating the viruses, and combining the immunogenic viral proteins TIV could also technically be called a subunit vaccine, since the antigenic proteins from three viral strains are combined together.

The ever-changing influenza virus requires a new vaccine every year

Evasion of humoral immunity by microbes Antigenic variation limits vaccine effectiveness

Creation of global pandemics by antigenic shift Fig. from Pathogenic Viruses, Sherris Medical Microbiology 6 e, 2014

1918 -1919 Influenza pandemic estimated to kill at least 20 -30 million people worldwide Image from John M. Barry, “The Great Influenza”

Artificial synthesis of novel Influenza viruses based on Recombinant DNA technology is designed to speed up manufacturing of vaccines. Traditionally, viruses had to be grown before being shipped to manufacturer-time consuming (see graph below) Sending DNA sequence of novel virus electronically to manufactures allows for rapid virus growth and vaccine development within weeks, rather than months. Traditional method of growing novel influenza virus before shipping to manufacturer was shown to be too slow.

Production of live, attenuated viruses Viruses easier to attenuate than bacteria, due to their smaller genome

Attenuated vaccines Examples: Sabin vaccine (OPV), LAIV, MMR and Chickenpox (Varicella) vaccines OPV=Oral Polio Vaccine MMR=Measles, Mumps and Rubella viruses LAIV - Live Attenuated Influenza Vaccine, not recommended by CDC for 2016 -2017 BCG vaccine- attenuated strain of M. bovis, used to treat against M. tuberculosis BCG- (Bacille Calmette-Guerin vaccine) Multiple mechanisms exist for producing an attenuated pathogen -repeated passaging outside of human body, or outside of human cells -repeated passaging at lower temperatures (30 C) -growth in eggs or other animal -inactivation of virulence factors by chemical treatment, e. g. formaldehyde, formalin

Successful vaccination campaigns can eradicate some human-dependent pathogens FYI: Last recorded case of polio was in 1979. As of 2016, poliovirus thought to be present only in Nigeria, Pakistan and Afghanistan

Salk (killed) and Sabin (attenuated) vaccines for polio both used to eradicate polio from USA Current efforts by WHO and others to eradicate polio from planet are ongoing; www. cdc. gov/polio/updates

Attenuated and Inactivated vaccines each have advantages and disadvantages be familiar with the list below

Subunit vaccines Examples: Hepatitis B virus, DTa. P, Diphtheria, Tetanus and Pertussis bacteria The immune system has evolved to react most strongly against important virulence factors of pathogens, such as bacterial exotoxins or viral proteins required for attachment. Subunit vaccines are advantageous because they do not cause infections and pose little risk to immunosuppressed individuals. Many bacterial subunit vaccines are directed at inactivated toxoid form of bacterial toxins, since it is difficult to provide an inactivated or attenuated bacteria as a vaccine. Useful definitions below in notes.

HBs. Ag – Hepatitis B surface antigen used in HBV subunit vaccine Hbs. Ag artificially expressed in yeast cells, avoids risk of contaminating HBV Fig. from Ryan K et al. Sherris Medical Microbiology, 3 rd Ed.

DTa. P vaccine – contains 3 toxoids for prevention of diphtheria, tetanus and whooping cough. DTa. P refers to subunit components of bacteria Bordetella pertussis Original DTP vaccine contained inactivated B. pertussis bacteria, yet complications associated with inflammation led to preference for the DTa. P vaccine. Corynebacterium diphtheria – cause of diphtheria, a respiratory disease, diphtheria toxin cause heart and nerve cell damage Clostridium tetani – cause of tetanus, tetanus toxin causes spastic paralysis. Bordetella pertussis – respiratory disease, pertussis toxin causes death of ciliated respiratory epithelium

Conjugate vaccines used to increase immune responses against capsules Figure from Kaplan USMLE Step 1 review for Immunology and Microbiology

Haemophilus influenza B (Hib) and Streptococcus pneumoniae (pneumococcus) prevented by conjugated vaccines Panels go from left to right

Rotarix and Rota. Teq – 2 effective rotavirus vaccines: Rotarix – attenuated virus Parham Fig. 14. 12

Rota. Teq–combination of cattle rotaviruses genetically engineered to express viral proteins that cause human disease Parham Fig. 11. 19

Adjuvants augment systemic or mucosal immunity by activating innate immunity a couple of bacterial proteins will not activate innate immunity. Adjuvants help activate innate immune system

Aluminum salts (alum) – most commonly used adjuvant in USA Monophosphoryl lipid A – also used in the Cervarix ® vaccine for HPV Future adjuvant research may help steer immune responses to a Th 1 or Th 2 response

Understanding how to steer immune response will help create better vaccines One complication in studying how some people effectively fight diseases, is that they don’t seek medical attention if they don’t get really sick Parham Fig. 11. 27