2.5 - Emerging Infectious Diseases

Experts predicted next epidemic start in animals (USA Today, October 22, 2008)

-First known case Swine Flu/H1N1: March 28, 2009. •First known case in US: April 17, 2009. •April 26th: New Zealand, France, Israel, Brazil, Spain report cases. 86 deaths in Mexico attributed to swine flu. •June 11th: Pandemic declared by WHO. •July 14th: WHO authorizes Pharma to manufacture vaccines. •August 27th: US colleges see spike in number of cases including RPI. •September 4th: WHO announced 625 deaths in the last week. •October 5th: vaccine ready. •October 24th: President declares a national emergency. •Spring 2010: decline in H1N1. •Fall 2016-Winter 2017: H7N9 new bird flu but chickens only. •Spring-Summer 2022: Highly Pathogenic but chickens, turkeys, etc. Wild waterfowl birds carry but were not sick.

5 Stages of Zoonotic disease transmitting to humans

1) Agent only in animals 2) Primary infection - only animals infect human 3) Limited outbreak - From animals (or few cycles) or humans 4) Long outbreak - From animals or (many cycles) or humans 5) Exclusive human agent - Only from humans

What is H1N1 or NxNx? Influenza A Most Common

1918: human Influenza A (H1N1) pandemic, killed 50M people worldwide, Cedar Rapids Swine Show (Iowa) 1931: documented infectious transmission 1933: Used ferret model to document transmissibility for human & swine viruses 1918-present: Evolution of virus in humans. 1957: H1N1 abruptly disappeared from human population 2009: Re-emerged leading to pandemic Continued to track for re-emergence in humans

2014 Ebola Outbreak: Genomic surveillance to determine origin and transmission

2014 Science 345, 13690-1372 58 co-authors including Lina Moses Pardis Sabeti was corresponding author Sequenced 99 Ebola virus genomes from 78 patients in Sierra Leone. Five co-authors died from Ebola. Rapid accumulation of interhost & intrahost genetic variation West African variant diverged from central African lineages 2004. Crossed from Guinea to Sierra Leone May 2014 Sustained human-to-human transmission by contact bodily fluids - Traditional burials involve touching and kissing deceased. No evidence of additional zoonotic sources

New Ebola Outbreak: July-August 2018 Democratic Republic of the Congo (DRC)

26 cases, 20 deaths July. Another outbreak August 2018 October 2nd: 161 cases & 105 deaths Concern is location (war zone) & may spill into Uganda and Rwanda Approval to use Ebola vaccine from Merck Epidemic now: Uganda has has as many outbreaks as DRC Monitoring stations at borders: checking temperature, Rebel fighting, unrest disrupt monitoring & treatment. Further complicated because a new species of Ebola just emerged in bats but not yet in humans Even if recover, long term physical and neurological effects New concerns. Nearly 60% of newly reported cases children

All Influenza A contain 8 RNA genes. Enveloped RNA Virus

8 segments as RNA 1) RNA polymerase PB2 2) RNA polymerase PB1 3) RNA polymerase PA 4) hemagglutinin HA (H1-H16) 5) Nuclear Protein NP 6) Neuraminidase NA (NA1-9) 7) matrix proteins M 8) nonstructural proteins MS HxNx based on HA and NA proteins -classified based on antigenicity of HA and NA proteins HA (16) binds cell's receptors and critical for fusion of viral & endosomal membranes NA (9), viral enzyme that facilitates virus release from infected cell

Vaccines are Dependent Upon Our Natural Immune System

Adaptive Immunity refers to the use of antibodies to defend the body from pathogens. "Custom tailored" to each specific invader. Antibodies circulate in the blood, lymphatic fluids, and interstitial fluids, and bind antigens on pathogens Antibodies (immunoglobins) are produced by B cells, a type of lymphocyte Millions of genetically distinct types of B cells, when a B cell detects an antigen, it converts it into a "plasma" cell to produce huge amounts of Ab's Other B cells become memory B cells and wait to attack their antigen

Small Interfering RNA (siRNA)

Are also noncoding, do not encode protein Double stranded RNA Typically 20-25 bp's with overhang Hybridizes perfectly with mRNA Typically function in cytoplasm Silences gene expression Cell defense against gene double stranded RNA viruses Can remodel chromatin Can establish patterns of methylation

Antigenic shift

Because RNA genome is segmented, allows influenza A viruses to undergo genetic recombination with other influenza viruses Leads to large changes in genetic makeup When viral strains undergo this, the immune system sees it as a new virus

Why do viruses undergo antigenic drift, shift or adaptation?

Because viruses are constantly mutating

Why are so many EIDs linked to viruses?

Because viruses have a high rate of mutation! Viruses lack the proofreading mechanisms seen in DNA

2014 Ebola Outbreak

Began Feb. 2014: - Feb: Guinea - March: Liberia - Late June: Nigeria - Emergence into major cities Largest outbreak: doubling period, 34.8 days August 15th: 2240 cases, 1229 cases documented Emergence into major cities increased transmission and viral evolution 2014-2016: 3,956 deaths & 10,168 survivors in Sierra Leone

Ebola: Not a Disease of the Developed World

Comes from Africa Ebola virus (EBOV) one of 5 ebolaviruses ssRNA: 19,000 nucleotides, 7 structural genes Lethal human pathogen: fatality rate ~78% Previous outbreaks confined to remote regions of central Africa Largest 1976: 318 cases 2014: Guinea, Sierra Leone, Liberia, Nigeria, Democratic Republic of the Congo

What You Need to Know to Predict an Outbreak?

Consider - interspecies transmissions & re-assortment of viral genome, human-to-human transmission Global perspective: How do you predict the next pandemic? We can watch virus evolution. -> large-scale sequencing, bioinformatic analysis, genomic approaches -> experimentally test recombinants for pathogenicity -> focus on the hotspots of disease outbreaks at the site of the outbreak H7N9: 2016-2017 Bird Flu - started in China, 460 people infected & 1258 died - announcement March 2017 that Tyson Foods chickens infected - destroyed 73,500 chickens at farm in TN - did not turn out to be the threat 2018-now

Covid-19: What is the Outlook Now & in the Future

Coronaviruses are a group that cause disease in mammals and birds There are 7 known human coronaviruses to date. 4 are endemic to people (common cold) 2003 SARS: Severe Acute Respiratory Syndrome - Infected cats, birds, bats - 1st case of cave bat to human transmission (genetically verified) - China to Canada then spread globally 2012 MERS: Middle East Respiratory Syndrome, "camel flu" - Bats to camels to humans 2019 COVID-19 outbreak in Wuhan, China - Bats original source

Where are siRNAs found?

Cytoplasm

Where are small noncoding RNAs found?

Cytoplasm

Where is miRNA found?

Cytoplasm

Contributing factors to growing EID problem

Demographic changes: population growth, inhabiting new areas Increasing human contact with wild & domestic animals 2/3 of EIDs originate from animals Behavior (drug use, sexual, hygiene) Poverty and social inequality (war, civil unrest, clean water, healthcare) Climate change and changing ecosystems (diseases of the tropics) Travel, commerce, and transportation Development of antibiotic resistance Increased risk from emerging zoonotic diseases

Small noncoding RNAs - MicroRNAs and Small Interfering RNAs

Do not encode protein Function in cytoplasm Block translation of the mRNA or promotes degradation of mRNA

The Reality of Global Trends - Emerging Infectious Diseases (EIDs)

EIDS are infections that recently appeared or whose incidence or geographic range is rapidly increasing or threatens to increase in the near future EID emergence thought to be driven by socio-economic, environmental, climate change, and other ecological factors Results from early 2000s skewed because of the lack of data collection in under-developed regions Comprehensive study published in 2008 in Nature

Recent EIDs

Flu vaccine is a mix against 3 or 4 strains A (early fall) and B strain (spring) Northern Hemisphere & Southern Hemisphere-specific vaccines 2020-2021: - Influenza A: H1N1 and H3N2 for early Sept - Feb - Influenza B: Yamagata and Victoria lineage late going into spring 194-198 M doses were available 2021-2022: - Influenza A: H1N1 and H3N2 for early Sept - Feb - Influenza B: Washington B Victoria lineage - Influenza B: Phuket Yamagata lineage 2022-2023: Egg-based & Cell/recombinant based - A/Wisconsin/2019 (H1N1); A/Darwin/2021 (H3N2) - B/Austria/2021-like B/Victoria lineage - B/Phuket/2013-like B/Yamagata lineage

Epidemiology: The Study of the Origin of Diseases: How They Spread & How to Prevent Their Spread

Geographic distribution of the disease Disease outbreaks can be endemic, sporadic, epidemic, or pandemic -Many of the most deadly pandemics have been caused by influenza viral strains The World Health Organization decides whether a disease outbreak is a pandemic or an epidemic

Examples of EIDs that were linked to viruses?

H1N1 - Influenza Ebola: hemorrhagic fever, single-stranded RNA Dengue fever - "bone breaking disease" -Migration from tropics to the Gulf Coast to Texas to CA Zika: infant brain disorders, microcephaly, Guillain-Barre Syndrome West Nile and other EIDs causing encephalitis HIV or AIDS: 2 individual single RNA strands SARS, MERS, & SARS-CoV-2: Single Stranded RNA DNA viruses: have DNA proofreading mechanisms: -mutate less frequently -hepatitis, chicken pox, herpes infections -vaccinations that control these

Zoonotic diseases

Infectious diseases transmitted from other vertebrate animals to humans

Vaccine Development Process 2020

More than 100 vaccine candidates under development with a number in human clinical trials 172 countries & multiple candidate vaccines. Global initiative, ACTIV Accelerating Covid-19 Therapeutic Interventions and Vaccines - 48 vaccines in clinical trials by 10/21/20 Preclinical testing: In cells & animals, does elicit immune response? Phase 1: small number people, is it safe? Phase 2: expanded to 100s split into 2 groups (children and elderly, male/female, diversity, different doses) Phase 3: Efficacy. To 1000's and placebo vs vaccine. Large enough #'s to capture relatively rare side effects. MUST Protect at least 50% of those who receive it US Regulatory Review began 10/22/20

New Ebola Outbreak: 2019-present Africa

New outbreaks in 2019 & 2020 October 14, 2020: Regeron's monoclonal antibody cocktail REGN-EB3, Inmazeb, approved by FDA and provided to DRC. Strategy to control outbreaks: ring vaccination Guinea outbreak in 2021 and another in Congo saw shift in strategy Normally see large number mutations if sustained outbreak - But ~dozen rather than >1000 mutations 2021 outbreaks seemed to have the signature from 2013-2016 infections Proposed that some individuals who had been infected in 2013-2016 had recovered, gone dormant, and reactivated to infect new people Proposed mass immunization program as prevention strategy

SARS-Cov-2 is a Single Stranded RNA Virus

One strand & not multiple segments Genome size is largest of coronaviruses: 27,000-34,000 bases. Name comes from the Latin corona, crown, or "halo" characteristic appearance of the viral particles Spike (S) Envelope (E) Single Strand RNA Nucleocapsid (N) Enters cell and "uncoated" RNA attaches directly to ribosome First protein synthesized. - RNA-dependent RNA polymerase to generate new RNAs Generates long poly-protein which is then cleaved into individual proteins required to assemble the virus

What Lessons Do We Need to Learn after recent Ebola Outbreak?

Pandemics will continue to occur with 3-4 year frequency Many/most will be zoonotic in origin Zoonoses originating from wildlife represent a significant threat to global health, security, and economic growth Must be a public health priority - Update a global database of emerging EID events. - Analyze the demographic, environmental, and biological correlates of occurrence - Improve surveillance and long-term EID monitoring programs - Design field experiments to test underlying mechanisms of zoonotic disease emergence Believe in science and vaccinations STEM education for all is the path forward

What Lessons Do We Need To Learn Overall?

Pandemics will continue to occur with 3-4 year frequency (Monkeypox as an example) Many/most will be zoonotic in origin Significant threat to global health, security, and economic growth Public health must be a priority: - Update a global database of emerging EID events - Continue to develop vaccines in advance - Improve surveillance and long-term EID monitoring programs - Testing is critical to prevent outbreaks - Develop global partners & work together Get Vaccinated STEM Education for all is the path forward

Things to remember about gene regulation

Prokaryotic gene regulation is different from eukaryotic gene regulation the former uses an operon and TFs, while the latter regulates expression using proteins TF activators/silencers - repressor used for lac operon

Other Strategies to Control COVID-19

Regeneron Monoclonal Antibody Cocktail: REGN COV2 binds virus & reduces viral load over 7 days Remdesivir: antiviral developed over decade ago to treat hepatitis C and cold-like virus called respiratory syncytial virus (RSV). Was not effective for either. - Was effective for Ebola, MERS, and SARS. - Works by interrupting one of key enzymes that virus needs to replicate RNA - Does provide some benefit especially in combination with other treatments - Accelerates recovery in severe cases

What did we learn by Early March 2020

Response: really fast to contain & define viral patterns Rapid response of China gave world ~1 month to prepare World Health Organization (WHO) announced pandemic 3/11/20 - WHO reluctant because of 2009 H1N1 pandemic. Backlash. World was not ready even US. - Lack of test kits with contact tracing, and necessary PPE - 2016-2017 White House dissolved pandemic/infectious disease experts and also cut funding. Did not listen to CDC Death frequency seemed really high at 4+% but based on total infections - If you don't see them, you cannot count them - Difficulty in getting the # infections and deaths early on

Emerging Infectious Diseases (EIDs) - A Growing Problem

Since 2008, new & resurgent infectious diseases have had a significant impact on human health They've been moving to new geographical areas - tropics to more northern hemispheres. More frequent and new EIDs

Antigenic drift

Small changes in a virus's genetic makeup. Not a new strain

micro RNA (microRNA)

Small single stranded RNA Typically ~22N's long Forms complex to bind to mRNA Requires 7-9 N's

Vaccine Efficacy - How Will it Perform in a Clinical Trial

US Food and Drug Administration (FDA) recommends that COVID-19 vaccines have an efficacy of >50% Efficacy is the reduction in cases among those vaccinated versus those that are not Phase 3 clinical trials: placebo versus vaccine COVID-19: - Johnson & Johnson 66% against disease, 93% against hospitalization - Pfizer 95% against disease. 100% efficacy adolescents 12-15 - Moderna 94% Shingix vaccine - Shingles: 97% overall efficacy in adults 50 & older. Seasonal flu vaccine: Typically, 30-60% dependent upon the year. Inactivated polio vaccine: 90-100% within 3 doses.

Viral adaptation

Virus can adjust to host such that evades cell defense mechanisms Takes over cellular metabolism for virus benefit

Where is tRNA located

cytoplasm and ribosome it carries mRNA to ribosome to create polypeptides

Endemic

disease is maintained in the population, wide geographic distribution. Ex. common cold

A sporadic disease outbreak

disease occurs occasionally in low numbers, not geographically confined, Ex. Tetanus, rabies, plague, measles

spike protein

help some viruses invade host cells; present in covid 19

Pandemic

new incidences of the disease increase & spread rapidly, very wide global distribution. Ex. HIV/AIDS, 1968 H3N2 (Hong Kong Flu), COVID-19.

Epidemic

new incidences of the disease increase rapidly, but geographically confined, Ex. SARS

Where is mRNA found?

nucleus and cytoplasm translated into proteins in the cytoplasm, transcribed from DNA and spliced (introns removed, exons spliced together) in the nucleus