Influenza -- Slide Set 9

Influenza -- Slide Set 9

1. First recognized pandemic in 1580. At least four in 1800s, 3 in the 1900s, and one in 2000s.

   • 1918-1919 pandemic: ~21 mill. deaths worldwide
     • Killed 6x more US citizens than WWI. Mostly young, healthy adults unlike other seasonal flus.
     • Caused a drop in the life expectancy graph for 1918.
   • Past pandemics caused by enough drifting of avian virus to infect humans efficiently, shifted virus with human and animal reassortment, and reemergence of viral strains not seen in a generation.
   • Potential impact of a pandemic in the US: 1/3 population infected (200 mill), 40 mill. outpatient visits, 700K hospitalized, 89K-200K deaths, $100 billion economic impact.
   • 2009 H1N1 pandemic: 61 mill infections, 274K hospitalizations, 12,470 deaths
     • Like 1918 epidemic, most complications in individuals under 65 years (older people may have had some memory to H1N1).
     • By comparison: seasonal influenza causes 200K hospitalizations and 36K deaths annually (mostly in 65+).
       • 10% of respiratory samples testing positive for flu - good indicator of start of flu season.
     • Sudden emergence, swift takeover of virus pool, and retreat as other strains reemerged. Strain prevalence fluctuates which makes it difficult (but not impossible) to predict dominant circulating strains.
     • 2009 H1N1 displaced every other strain (H3N2 and B). Now one of the regular seasonal variants (although 2010-11, H3N2 and B returned).
       • H3N2 became dominant in 2011-12. 2012-13, H3 dominated. 2013-14, 2009 H1N1 dominated again. 2014-15, back to H3N2. 2015-16, back to H1N1. 2016-17 (and 2017-18), back to H3N2.
         • 2017-2018 flu season resulted in large % of visits for ILI not too far from 2009 H1N1.
           • This year's vaccine wasn't too effective (36% overall) because mutations that occur in H3N2 viruses results more frequently in differences between vaccine and circulating viruses (compared with H1N1 or B).
             • Mutations in H3N2 viruses when grown in eggs more likely to result in antigenic changes (site mutates, Abs can't bind).

2. Virus first isolated in 1933, first cultured in eggs in 1936, allowing for first vaccine to be developed.

   • Inactivated vaccine (TIV): delivered by intramuscular injection, traditionally trivalent (A/A/B), quadrivalent approved in 2012-2013 (A/A/B/B), "split virus" and subunit types, duration of immunity 1 year or less
     • Most people get TIV.
     • Vaccine types vary: complete, viruses whose membranes have been disrupted by detergent (split virus), or subunit.
     • TIV protection depends on maintenance of high Ab titers. Duration is less than one year because of waning Abs and antigenic drift. If vaccine strains are well-matched to circulating strains, it is 70-90% effective in healthy persons <65 yrs.
       • In 65+, 30-40% effective in preventing infection, 50-60% effective in preventing hospitalization, 80% effective in preventing death.
     • Only induces Abs that circulate in the blood (IgG and IgM).
     • IIV adverse reactions: local (15-20%), systemic (<1%), allergic (rare), neurological (very rare).
   • Live attenuated influenza vaccine (LAIV): delivered intranasal, trivalent/quadrivalent, immunity lasts at least 1 year, approved for healthy persons 2-49 years (non-pregnant).
     • Works well in kids but not as well as TIV in adults. Never tested 50 and above.
       • In children: 87% efficacy in children 5-7 years, decreased fever and ear infection.
         • 2015-2016, LAIV less effective than IIV (inactivated); VE (vaccine effectiveness) lower than expected).
       • In adults: 20% fewer severe fever episodes, 24% fewer upper respiratory illness episodes, 27% fewer lost work days, 18-37% fewer days of healthcare provider visits, 41-45% fewer days of antibiotic use.
         • LAIV less effective in adults previously exposed to flu - preexisting Abs cross-react with weakened virus and prevent it from bestowing protective immunity?
     • Induces mucosal IgA to block infection. Can be administered concurrently with live or inactivated vaccines.
     • Potential risk: transmission of LAIV (mean shedding is 7.6 days, longer in children). Retained attenuated, cold-adapted, temperature-sensitive characteristics. No instances reported in the US.
       • LAIV adverse reactions: children (increased risk of wheezing in children 6-23mos), adults (increased rate of cough, runny nose, nasal congestion, sore throat, and chills). No serious reactions.
       • LAIV contraindications and precautions: <2yrs, 50+ yrs, chronic medical conditions, children and adolescents receiving long-term aspirin treatment, <5yrs with recurrent wheezing, immunosuppressed, pregnant. Should receive TIV if eligible.
   • Most US vaccines grown in fertilized chicken eggs since 1940s. 1 egg per strain, 3 per dose. Contains residual egg proteins and requires 6 months of lead time.
     • Cell culture vaccines approved in 2012 (faster, cheaper, and more flexible).
     • DNA-based vaccines in clinical trials.
     • "Universal" vaccines would target nonvariable epitopes.
       • Work in progress - targeting less-variable parts of HA (stem) to make "universal" vaccine.
         • Most protective Abs target head of HA, but it is very variable due to selective pressure from immune system. Stems are harder to reach.
     • "Master strains" of flu virus are kept (ability to grow to high viral titer in eggs). Coinfect an egg with target and master strain (vaccine "reassortant" strain with HA and NA from target and other genes from master strain).
       • Goal: strain that grows well in eggs and immunologically resembles the target strain.
     • Vaccine production process
       • (1) Surveillance (ongoing, global). (2) Strain selection (predict following year's dominant circulating strains). (3) Manufacturing and production (injection of eggs with virus strains). (4) Purification and testing (ensure virus is killed and vaccine is safe).
         • (5) Filling and packaging (vaccine released for distribution), (6) Shipping (Aug-Nov), (7) Vaccination (begins in October and ends in March usually).
       • Assessing vaccine efficacy: serological and clinical criteria.
         • Serological criteria: measuring anti-HA serum titers (IgG) in a HA assay - serum IgG levels are standard correlate of protection. Limited because inability to measure cellular immunity, mucosal Abs (IgA), and anti-NA responses.
         • Clinical criteria: ideally, RCTs with defined clinical outcomes. Observational studies are generally used (but have methodological limitations and may be influenced by case definitions, e.g. confirmed vs. ILI).
           • Study design, case definitions, and serological assays should be agreed upon by scientific/medical community to make vaccine trials more comparable.
         • Effectiveness depends upon protective efficacy of vaccine, transmission rate and disease severity, and vaccination practices and policy.
     • New vaccines should provider higher-level, broader protection but with comparable safety.
       • Improved control of influenza: increase utilization of current vaccines and develop vaccines with improved efficacy.
       • Alternative delivery methods: intradermally-delivered (enhance protection in elderly and allow for antigen sparing - 90% smaller needle), skin patches for remote self vaccination.
       • Alternative production: cell-culture has a faster turnaround time, safer for those with egg allergies, and less vulnerable (egg supply can be threatened by avian strains).
       • Subunit vaccine: using baculovirus as a vector (insert HA gene into genome), infect insect cells, cells produce baculovirus proteins and HA proteins. Doesn't need adjuvants to make strong response.

3. Virus envelope has two surface antigens: hemagglutinin (H) and neuraminidase (N).

   • Viral envelope derived from host cell. Virus breaks into cell, RNA enters nucleus, uncoats and makes copy of genome, produces viral particles, releases and uses cell membrane to make viral envelope.
     • Virus' hemagglutinin binds to host cell through sialic acid. Brought into cell through endocytosis. Virus escapes cell by using neuraminidase to cleave sialic acid.
       • Antibodies to head of HA prevent binding to sialic acid, antibodies to stalk of HA prevent virus from fusing, and antibodies to N prevent virus from leaving the cell.
         • Hemagglutinin inhibition assay (assay can't tell about immunity to neuraminidase). Mix RBCs into suspension: no Abs, compact button, Abs, cloudy. Infection of RBCs is an incidental activity (no benefit for flu viruses to infect them).
   • Hemagglutinin is more abundant on cell surface than neuraminidase - we've traditionally focused on anti-HA antibodies to measure vaccine efficacy.
   • Changes occur over time due to antigenic shift (swapping of genomic segments with another viral subtype) and antigenic drift (accumulation of point mutations).
     • Antigenic drift occurs partially because the enzyme used (RNA polymerase) to replicate the genome has a low fidelity/no proofreading function.
       • Minor change, subtype remains the same.
       • Most viral mutations occur in HA and N proteins (and in HA, mostly in the head).
       • Natural immunity: epidemiologically significant drift can result in more severe, early onset epidemics.
       • Vaccine-induced immunity: additional drift during production can impact vaccine effectiveness (and in different populations, e.g. elderly) especially with a particularly pathogenic strain. Lower antigenic distance, higher vaccine efficacy.
       • Reducing the impact of antigenic drift - cross-protective vaccines. Can use alternative antigens that are more conserved (M2 ion channel protein, nucleoprotein/NP), less variable regions of H and N antigens, intranasal immunization using LAIV (higher efficacy against drifted strains in children), adjuvanted vaccines, and alternative vaccines (virosomes, DNA vaccines, etc.)
         • Adjuvanted vaccines: alum, MF59, and AS03 good candidates. Allow for better immune response in vulnerable populations and antigen sparing (need less antigen).

4. Three major types of influenza: A, B, and C.

   • Influenza type A: Classified based on combination of H and N (e.g. H1N1, H3N2). 18 H subtypes and 9 N subtypes discovered.
     • Viral genome: single-stranded negative-sense RNA. RNA is segmented: one protein, one segment.
       • Allows for "antigenic shift" in which virus swaps segments of itself with the infected host cell.
         • Major changes introducing new genes (such as new H and N subtypes).
           • Because only H1, H2, and H3 subtypes can infect humans efficiently (HA required to infect cell), if an avian virus acquires H1 through shift, it can be devastating for humans.
         • Occurs at irregular intervals (10-40 yrs).
         • Exchange of gene segments between human and animal flu viruses can result in pandemics.
       • 8 segments of RNA that code one protein (or more) each.
     • Infects both humans and animals.
     • Major reservoir: DUCKS (waterfowl).
     • Moderate to severe illness in humans, affects all age groups
     • High degree of antigenic variation
   • Influenza type B: infects humans only (mostly children); typically milder disease.
     • Less genetic variability.
   • Influenza type C: rarely reported in humans, no epidemics.
   • A > B > C

5. Virus transmitted by respiratory aerosols and direct contact with contaminated objects. Replicates in respiratory epithelium.

   • Virus is contained usually in respiratory tract, but symptoms are systemic. Shedding lasts for 5-10 days.

6. 50% of infected develop classical clinical symptoms: abrupt onset of fever, weakness, muscle aches, sore throat, cough, runny nose, headache

   • Incubation period is 2 days (range 1-4).
   • Severity of illness depends on prior experience with related variants (closely related to strains with which we have memory - may have shortened infection).
   • Major symptoms last 2-3 days, but lack of strength/energy can last for weeks.
   • Complications of flu: pneumonia (primary influenza viral, secondary bacterial), Reyes' syndrome in children (given aspirin), myocarditis, worsening of pulmonary disease, death (0.5-1/1000)

7. Flu in US from 1990-1999: ~36K flu-related deaths each flu season, more than 200K flu-related hospitalizations. Most complications in ages 65+ (more than 90% of deaths).

   • Higher hospitalizations and mortality during H3N2 (type A) dominating seasons.
   • Cost of severe epidemics: $12 bill.
   • Flu is not usually actively diagnosed; usually count people who come down with influenza-like illness (ILI) during flu season (seasonal peaks in Jan-Feb).

8. Influenza vaccine is recommended for: healthcare providers, employees of long-term care facilities, persons with chronic medical conditions, household contacts of high-risk persons, providers of essential community services, persons traveling outside US, and persons residing in an institutional facility

   • Vaccination among healthcare providers: 2007-08 (48%), 203 highest with mandate (88.8%)
     • Those who choose to vaccinate tend to believe the benefits outweigh the costs.
   • Influenza vaccine contraindications and precautions: severe allergic reaction to vaccine component, moderate-severe acute illness, history of Guillain Barre syndrome within 6 wks following previous dose of TIV