Vaccines. December 9, Dan Stetson

Transcription

1 Vaccines December 9, 2016 Dan Stetson 441 Lecture #27 Slide 1 of 27

2 Final Announcements Exam Review Session: Tuesday, Dec 13, 11:30 AM-1:20 PM, T-639 Lecturer and TA evaluations: please submit them online (extra credit) Last submission time: December 18 Final Exam: Wednesday, December 14, 8:30-10:20 in T-435 (here) 60 questions (ten more than usual, 60 extra minutes) NOT cumulative: exam will cover lectures Thanks for a great quarter! Good luck! Happy Holidays! 441 Lecture #27 Slide 2 of 27

3 Infectious diseases are the second biggest killer worldwide 2004 WHO Statistics, worldwide Cause % of Deaths 1. Cardiovascular diseases Infectious disease Cancer Respiratory diseases Unintentional injuries 6.23 Low-income, developing countries 1. Lower respiratory infections Coronary heart disease Diarrheal diseases HIV/AIDS Stroke Chronic obstructive pulmonary Tuberculosis Neonatal infections Malaria Prematurity / low birth weight Lecture #27 Slide 3 of 27

4 Vaccines: the greatest triumph of Immunology Best Example: Smallpox a scourge from ~5,000 BCE through Oct 26, 1977 High mortality (up to 90%), disfiguring, extremely virulent 18 th century Europe: leading cause of death (400,000 dead per year) Vaccination (Jenner, 1796) effective but not broadly accepted 1967: million cases worldwide, 2 million deaths. WHO announces global eradication plan in 1967 (spearheaded in large part by William H. Foege, MD University of Washington) 10 years, 465 million vaccine doses, 27 countries: last natural case on Oct 26, 1977 *Sept 11, 1978: one death in UK from an escaped lab strain NOW: No cases in 34 years, viral stocks in two places: US CDC; Koltsovo, Russia 441 Lecture #27 Slide 4 of 27

5 Vaccines protect against a variety of devastating diseases Sam Stetson, 11 months 2014: : 2, : 48,277 *Most residual cases are in unvaccinated individuals (measles, mumps), or long after vaccine wore off (pertussis), or both. 441 Lecture #27 Slide 5 of 27

6 Pertussis is on the rise again 441 Lecture #27 Slide 6 of 27

7 Recent Outbreaks of Vaccine-Preventable Diseases, USA Pertussis (whooping cough) Measles Mumps 441 Lecture #27 Slide 7 of 27

8 Map of Median Incomes in the United States, 2008 The areas with outbreaks tend to be MORE affluent!!! 441 Lecture #27 Slide 8 of 27

9 Vaccines and autism: there is NO documented connection Original report: Andrew Wakefield et al: Lancet, 1998;351: Suggested a causal role for the MMR vaccine in autism and intestinal disorders. Retracted, 2010: Lancet. 2010;375:445. Dozens of ACTUAL epidemiological studies found no increased risk of autism after vaccination. The best: Madsen et al, N Engl J Med 2002; 347: Denmark: EVERY child has extensive medical records. ~540,000 children examined between 1991 and 1998 (440K vaccinated, 97K not vaccinated). NO increase in autism among MMR-vaccinated children; in fact, a slight decrease. Extended to thimerosal preservative (ethylmercury): NO increased risk of autism. Excellent Frontline episode on vaccines: Important points: Correlation does NOT equal causality (think about pirates and global warming) Complacency and ignorance are enabled by the very SUCCESS of vaccines! 441 Lecture #27 Slide 9 of 27

10 Vaccines: HUGE room for improvement ALL good vaccines were discovered empirically, after extensive (and costly) trial and error We really don t know why few vaccines work and most do not There are very few rules for effective vaccine design 441 Lecture #27 Slide 10 of 27

11 Safe relative to the disease: Examples: Smallpox: major side-effects, scars Old Pertussis vaccine (DPT): rash, fever, irritability (New pertussis vaccine (TDaP) fewer side effects but not as good) Neutralizing antibodies underlie the long-term protective effects of nearly ALL good vaccines T-dependent antibody responses most important, but cellular immunity also contributes 441 Lecture #27 Slide 11 of 27

12 Types of Vaccines I: the holy grail 1. Live attenuated vaccines: mostly viruses A strain or isolate of a virus that initiates but cannot complete its infectious cycle in a normal (immunocompetent) host These are generally the best vaccines: robust, long-term memory, excellent recall responses, elicit great antibody titers, many antigens targeted Examples: Oral Polio (Sabin), Measles, Mumps, Rubella (MMR), Smallpox, Varicella (chicken pox) Can be derived from a related virus that infects another host: cowpox -> smallpox These are rare and require strongly cross-reactive immunity Current methods for attenuating virus: serial passaging in heterologous cells 441 Lecture #27 Slide 12 of 27

13 Some issues with live attenuated viruses 1. Few viruses are amenable to attenuation Heterologous cell culture systems don t exist for most viruses The future : 2. Viruses are attenuated in healthy people but can cause disease in immunocompromised people 3. Risk of reversion, especially for viruses with ill-defined attenuation Example: oral polio vaccine (Sabin 3): only 10 out of 7429 nucleotides (0.1%) are different *circulating vaccine-derived poliovirus (cvdpv) is An emerging issue in developing countries with low vaccine coverage: New methods for defined genetic changes hold promise for currently intractable viruses 441 Lecture #27 Slide 13 of 27

14 2. Killed Vaccines: viruses, bacteria An infectious strain that is killed with heat or chemicals Examples: Influenza A, rabies, bubonic plague (Y. pestis), Hepatitis A These are usually safer, but not nearly as good as live attenuated vaccines: antigen loss, PAMP loss, no infection, rapid waning of protective immunity How to make seasonal flu virus: Types of Vaccines II A. Go to rural China and find out which strains are circulating B. Isolate the most prevalent strains C. Infect Chicken eggs D. Harvest virus, treat with formalin, mix with adjuvant (PAMP), add preservative E. Repeat next year (why?) F. Consider what would happen to flu if people stopped co-housing chickens and pigs 441 Lecture #27 Slide 14 of 27

15 Types of Vaccines III 3. Subunit Vaccines: viruses, bacteria Specific proteins from the microbe, but not the live microbe Examples: Hepatitis B virus, Human Papilloma Virus (Gardisil cervical cancer) Pros: Cons: Very safe (no infection), low toxicity Usually not nearly as good as live attenuated vaccines Restricted antigens (many microbial proteins are unstable in isolation) Limited to proteins since glycosylation patterns may differ in producer cells Must be mixed with adjuvants (PAMPs) not that many approved in humans Vehicle for delivery can create unintended consequences Case in point: HIV STEP Vaccine Trial (halted in 2007) Trivalent, cloned into Adenovirus 5 3,000 high-risk, uninfected males and females 441 Lecture #27 Slide 15 of 27

16 Why was the STEP trial halted? Total new infections Viral setpoint in infected individuals The increase in HIV infection of vaccinated subjects correlated strongly with preexisting antibodies to Adenovirus 5 (~40% of Europeans and ~90% of sub-saharan Africans have neutralizing Ad5-specific Abs) Possibly recruited more activated/memory CD4 T cells to mucosal sites 441 Lecture #27 Slide 16 of 27

17 4. Toxoid Vaccines: bacteria Made from inactivated toxic compounds; these toxins, rather than the live microbe, are responsible for disease Examples: Diptheria, Tetanus Types of Vaccines IV and V Pros: Cons: Usually very efficient, toxins ~easy to isolate, elicit good neutralizing Abs Specialized form of vaccine 5. Conjugate Vaccines: bacteria Chemical coupling of a bacterial polysaccharide to a protein (specialized for non-protein antigens) Examples: Haemophilus influenzae type B Reason: polysaccharides usually induce T-independent antibody responses: No CSR or affinity maturation TI-2 responses are weaker/absent in infants Conjugation to protein converts the response to T-dependent through linked recognition 441 Lecture #27 Slide 17 of 27

18 Pathogen features influence eradication efforts Smallpox as an example: a confluence of an effective, stable, cheap attenuated vaccine and key features of the virus 1. Smallpox had no hosts other than humans Zoonotic pathogens: pathogens that can be transmitted to humans from other vertebrate animals (or vice versa, less common). 60% of the ~1415 human pathogens are zoonotic. Influenza A Toxoplasma Rabies Yersinia pestis (bubonic plague) Borellia burgdorfori (Lyme Disease) **Of these, only flu is transmitted from human to human, we are dead end hosts for the rest 441 Lecture #27 Slide 18 of 27 Stetson 12/9/2016

19 Non-zoonotic diseases Malaria: Malaria is a vector-borne disease, but humans are still the only vertebrate host Humans are required for malaria parasite to complete life cycle Legionella pneumophila: Other host is an invertebrate, but this still poses a challenge for vaccines 441 Lecture #27 Slide 19 of 27

20 Pathogen (and political) features influence vaccine efficacy 2. Smallpox had no persistent phase and no asymptomatic carriers People were either killed or recovered (with disfigurements and/or blindness) Contrast: herpesviruses and HIV long latency, often asymptomatic 3. Smallpox induced long-term immunity in survivors Contrast: Influenza A, Malaria, Tuberculosis, which can reinfect and cause morbidity repeatedly. HIV: very few people (if any) naturally eliminate the virus once infected 4. Smallpox was fearful enough that a unified response was mobilized Even overcame less than ideal side-effects of vaccinia virus Contrast: Respiratory infections: usually young, old, immunocompromised 5. Smallpox was a sufficient threat (real or perceived) to wealthy countries Contrast: Malaria, cholera (diarrhea) are almost entirely confined to the developing world 6. There were no effective treatments for Smallpox Contrast: HIV (HAART); TB (antibiotics) for those who can AFFORD them! 441 Lecture #27 Slide 20 of 27

21 What about the diseases for which there are no vaccines? HIV M. Tb Malaria Respiratory 1. No zoonotic host /X 2. No asymptomatic carriers X X 3. Long-term immunity in survivors X X X X 4. Fearful enough to mobilize money 5. Major threat to wealthy countries 6. No effective treatments X +/- X X +/- X X X +/- /X 441 Lecture #27 Slide 21 of 27

22 Vaccine success depends on: A. Properties of the vaccine itself: Safety Efficacy at inducing long-term protective immunity Cost per dose Stability B. Properties of the pathogen being targeted: Host range Asymptomatic carriers/latency Long-term immunity in survivors, rate of reinfection C. Political, financial, social factors: How devastating is having the disease? Existing treatments (for wealthy people)? How is the disease contracted? (STDs, drug use, etc) Overcoming ignorance and misinformation (MMR and autism) 441 Lecture #27 Slide 22 of 27

23 HIV vaccine: challenges on every front Vaccine: Currently not possible to develop live attenuated versions of HIV Vaccines that elicit neutralizing antibodies don t work because of efficient cell-cell transmission No small animal models for HIV infection and vaccine testing **We are only now learning how the innate immune system detects HIV within infected cells Virus: HIV mutates very frequently: not one virus but countless quasispecies (antigen drift) Long asymptomatic carrier phase these carriers transmit HIV depletes the very cells that are required to provide long-lasting immunity Social/political/intellectual: HAART works very well in people who can afford it (even this is huge economic burden) HIV is transmitted by sex and drug use (and transfusions rare now) There are still people who believe HIV does not cause AIDS 441 Lecture #27 Slide 23 of 27

24 The future: Rules -based design of better vaccines The toolbox: Immunology: knowledge of key innate and adaptive immune pathways Toll and TLRs: (Hoffman, Medzhitov and Janeway) TLR4 and LPS: 1998 (Beutler) TLR9 and DNA: 2000 (Akira) TLR3 and dsrna: 2001 (Medzhitov, Flavell) TLR7 and ssrna: 2004 (Reis e Sousa, Hartmann) RIG-I/MDA5: 2004 (Fujita, Gale) Intracellular DNA sensing: 2006, 2009, 2013 (Medzhitov, Barber, Chen) Regulatory T cells: (Sakaguchi, Rudensky) Th17 cells: (Cua, Stockinger, others) Microbiology: pathogenicity, activation, evasion, manipulation of innate immunity Together: Host-microbe interactions that underlie infectious disease and illuminate new strategies for making better vaccines Most of these specific advances have occurred within the last decade 441 Lecture #27 Slide 24 of 27

25 Using innate immunity to design better vaccines A vaccine should trigger the same module as the pathogen 441 Lecture #27 Slide 25 of 27

26 Why are live-attenuated vastly better than killed/subunit vaccines? Attenuated vaccine: YES YES Killed vaccine: YES NO 441 Lecture #27 Slide 26 of 27

27 At what point(s) might live attenuated viruses be better? Live attenuated vaccines Killed/subunit vaccines CD8 CD4 (Infected cell) 1: Antigen and PAMP source 2: CTL target identification CD8 Effector CTL 441 Lecture #27 Slide 27 of 27