EMERGING DISEASES

infections that had appeared in a population for the first time, or that may have existed previou

sly but is rapidly increasing in incidence or geographic range.

Re-emerging diseases
-infections that had decreased in incidence in the global population and was
brought under control through effective health care policy, reached a nadir, and, mo
re recently, began to resurge as a health problem (i.e.Measles)
Causes
Environmental
Global warming
Climate change
Social
urbanisation

VIRUS
Changes in
human demograph HOST Viral variability
ics and trade/
travel
Diagnostic
Comportamental methods
Human susceptibility Breakdown of
Aging public health
Immunodeficiency systems
AGEING
INTERNATIONAL TRANSPORT
WUHAN, Hubei, China
11 million population

Wet market
 CHANGES IN MICROORGANISMS

• Introduction of a “new” pathogen

• Zoonotic transmission
• Coronaviruses- SARS / MERS/ SARS CoV-2
• Arboviruses: Zika virus
• Viral Hemorhagic fever (VHF) – Ebola

• Crossing the Species Barrier- prions, HIV

• Mutants with high virulence of a common pathogen – flavivirus
es (West Nile), enteroviruses 71, D68
• Microbial adaption of an “old” pathogen - genetic drift and geneti
c shift in Influenza A
Coronaviruses
120nm, enveloped (+) ssRNA viruses
(27-32 kb)

Structural Proteins
S (spike) , E (envelope),
M (membrane), N (nucleocapsid)

16 nonstructurale proteins (nsp1–16),

5-8 accessory proteins

Replication- ARN polymerase (RdRp)- High recombination capacity

Low Variability - Nsp 14 exoribonuclease

 Alphacoronavirus:
HCoV-229E Betacoronavirus:
HKU-NL63 Lineage 2C:
MERS CoV

Betacoronavirus:
Lineage A:
HCoV-OC43
HCoV-HKU1

Betacoronavirus:
Lineage 2B:
SARS CoV

Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev
Microbiol. 2019;17(3):181–192. doi:10.1038/s41579-018-0118-9
Chan et al, Trends Microbiol, 2013; Cheng et al, Clin Microbiol Rev, 2007; Chan et al,
Clin Microbiol Rev, 2015; Woo et al, J. Virol, 2005
 Origin: African bats
Intermediate host -HCoV-229E camels

Origin: rodents

SADS -Swine acute diarrhoea syndrome

origine -Rhinolophus bat coronavirus
HKU2- no human infection

Cui J, Li F, Shi ZL. Origin and evolution of pathogenic

coronaviruses. Nat Rev Microbiol. 2019;17(3):181–192.
doi:10.1038/s41579-018-0118-9
ZOONOTIC SPILLOVER

SARS HuCoV, MERS HuCoV

-Variants of bats betacoronaviruses

-intermediate host - Palm civet/ dromedary camels/unknown

- Incidental human transmission
-efficient secondary human to human transmission
 3 NEW ZOONOTIC CORONAVIRUSES
SARS - Severe Acute Respiratory Syndrome 2003-2004
8 000 cases- 774 deaths

MERS- Middle East Respiratory Syndrome 2013-2019

2 428 cases - 838 deaths

SARS CoV-2 COVID-19

> 42.6 millions cases - 1,145,198 deaths
(24.10.2020)
 SARSCoV –2003

Asian civets- Kopi Luwak African civets-mosk

Palm civet

Small mammalian/ exotic dishes /High antibodies titers in people working in exotic food markets
Coronaviruses interpersonal transmission- respiratory droplets=>Rapid transmission
Symptoms: fever /dry cough/ headache/ muscle stiffness/ malaise/ loss of appetite/ confusion
high mortality rate (~10%)
 Viral Genome Sequencing
=> Phylogenetic tree

Hoffmann M. et al, Cell DOI: (10.1016/j.cell.2020.02.052)

November 2002 1. SARS - Severe Acute Respiratory
Guangdong,China-severe atypical Syndrome
pneumonia
-international report
February 11, 2003 (305 cases, 5
deaths)
March 12, 2003 - WHO global alert
- > 8,000 patients, 774 deceased
(mortality 9.5%), 26 countries

Dr Liu Jianlun
- Disappeared in 2004- efficient public health measures
screening travellers for fever -infrared thermometers at airport customs an border checkpoints
 1. SARS - Severe Acute Respiratory
November 2002 Syndrome
Guangdong,China-severe atypical
pneumonia
-international report
February 11 2003 (305 cases, 5
deaths)
March 12 WHO global alert - >
8,000 pacienti, 774 decese
(mortality 9.5%), 26 countries

- Disappeared in 2004- efficient public health measures

- Possible viral mutation- attenuation of replication by a 29 nucleotide deletion in orf8
gene acquired during the early stages of SARS-CoV
Muth D, Corman VM, Roth H, et al. Attenuation of replication by a 29 nucleotide deletion in
SARS-coronavirus acquired during the early stages of human-to-human transmission. Sci Rep. 2018;8(1):15177..
doi:10.1038/s41598-018-33487-8
2. MERS- 2012 in South Arabia/ 2013- 2019
2494 cases - 858 deaths (mortality rate 35%)

Intermediate host –camels (serologic proof of infection

from 1983)
3. SARS CoV-2 – COVID 19
January 2020 Wuhan >11 millions inhabitants, Hubei,
China.

A cluster of 45 atypical pneumonia reported at the end

of December, in China cases hospitalized from the end
Nov- early WHO response
->>COVID 19 (Coronavirus Disease 2019).
 ORIGIN
SARS CoV-2 -BatCoV RaTG13- 96.3% genetic similarity
intermediate host- unknown

Trafficked Malayan pangolins- coronavirus strain highly related

with SARS CoV-2
- independent evolution of bat derived viral strains in humans and
pangolins?
Genomic analysis SARS CoV 2:
• Evolved in the present form by natural selection
- Zoonotic spillover directly in the pathogenic human form,
selected in an intermediate host
- Zoonotic spillover in an initially non/less pathogenic form and
further evolution during human to human transmission- marked
increase in transmissibility

SARS CoV-2 isolates- very homogeneous nucleotidic sequences –

recent introduction in humans – no significant mutations
Hoffmann M. et al, Cell DOI:
(10.1016/j.cell.2020.02.052)
SARS CoV and SARS CoV 2- receptor:ACE2

MERS CoV- receptor -

Dipeptidyl peptidase 4
(DPP4, CD26)
 ACE2 physiologically counters
RAAS (renin–angiotensin–
aldosterone system) activation,
metabolizing angiotensin II (a potent
vasoconstrictor) to generate
angiotensin-(1–7) (a vasodilator).

ACE2 also cleaves angiotensin I to

angiotensin(1–9) and participates in
the hydrolysis of other peptides.

• Clinical trials to test the safety and efficacy of RAAS modulators, including recombinant
human ACE2 and the ARB losartan in Covid-19
• Abrupt withdrawal of RAAS inhibitors in high-risk patients, including those who have heart
failure or have had myocardial infarction, may result in clinical instability and adverse health
outcomes
• Until further data are available, RAAS inhibitors should be continued in patients in otherwise
stable condition who are at risk for COVID 19

Vaduganathan M et al Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med 382;17 nejm.org April 23, 2020
 Gp S (spike) trimeric, metastable conformation
S1-RBD
S2- fusion

ACE II ()- metalopeptidase TMPRSS2-

- epitelial bronchial cells, type II pneumocytes type II transmembrane serine
- extrapulmonary (upper respiratory tract, oral and ocular protease – S protein priming-
mucosa, GI and renal tract, vascular endothelia) infectivity activation
 SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2-
conformational modifications that facilitated human transmission :

Mutations in the RBD Functional polybasic (furin) cleavage

of SARS-CoV-2 site at the S1–S2 boundary

Predicted acquisition
of 3O-linked glycans
around the site

Andersen, K.G., Rambaut, A., Lipkin, W.I. et al. The proximal origin of SARS-CoV-2. Nat Med 26, 450–452 (2020). https://doi.org/10.1038/s41591-020-0820-9;
Zhang T, Wu Q; Zhang Z. Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak Current Biology, Volume 30, Issue 8, 20 April 2020, Pages 1578;
Pathogenesis
• High viral load during the first week,
• Host immune response (innate and acquired immunity) overactivation
contributes to the pathogenesis of COVID-19

Activated host immunity

• Lymphopenia- neutrophil-to-lymphocyte ratio (NLR) -predictive for severe
COVID-19
• Dysfunctional immune responses to virus-specific antigen
• Robust acquired anti-IgG response –>> viral clearance, but can lead to
immune-mediated tissue damage.
• Cytokine release storm (CRS)
 Cytokine release syndrome

Monocyte, macrophage, dendritic cell

activation
IL-6 release - instigates an amplification
cascade

increased systemic cytokine production

contributes to the pathophysiology of
Humanized
severe COVID-19,
Mab acting as
hypotension
an IL6R
acute respiratory distress syndrome
antagonist
(ARDS)

IL1 blocking- anakinra; Jak kinase

Moore JB, June CH Science 2020;368:473-474

Transmission
- Respiratory droplets released in the respiratory secretions when a person with infection
coughs, sneezes, or talks
-direct contact -person touches an infected surface and then touches his or her eyes, nose,
or mouth.
Droplets typically do not travel more than six feet (about two meters) and do not linger in the
air- experimental model experimental –the virus persists in the air up to 3h – airborn
transmission? –universal precautions for airborne pathogens in hospitals (endotracheal
intubation, bronhoscopy, aerosolized drugs)
- Asymptomatic/ pre-symptomatic transmission (1-3 days before symptom onset)
- Persons on flights from Wuhan,
- Long term care institutions Washington, SUA.
Diamond Princess cruise ship- 634 de persons confirmed with SARS CoV-2
52% did not present symptoms at testing.
18% remain asymptomatics
How contagious the infectious disease is (R0):
• Length of virus shedding
• Transmission opportunity (crowding, close social contacts),
• Individual susceptibility
• “Superspreaders”
High transmissibility 2 days before symptoms, decrease after 8 days virus
shedding 28 days (isolated cases probably unviable)
Seasonality - yes for influenza viruses, some coronaviruses, but not compulsory
(animal coronaV do not show seasonality) –impredictable for SARS CoV2
Mortality rate- increases with age and comorbidities-> 60 ys- 3-5 x higher
 Mathematical model Imperial College London
predictions
- self-isolation
- Social distancing,
- School closures,
- quarantine
- Wear masks

possibly intermittent maintained until herd

immunity or vaccine
Gandhi M, Rutherford GW, Facial Masking for Covid-19 — Potential for “Variolation” as We
Await a Vaccine NEJM, 2020, DOI: 10.1056/NEJMp2026913
 + CDC - Rapid Tests for detection of viral Antigens

Patel et al. mBio 2020; doi:10.1128/mBio.00722-20

 Treatment

High VL
• Remdesivir*- FDA approved
since 24.10. 2020
Hyperinflammatory syndrome
• Favipiravir -Dexametasone
• Mab anti S • Mab anti receptor IL-6 (tocilizumab) , anti IL1 beta
• Convalescent Plasma (Anakinra)
• Nebulized IFN beta
Coagulopathy
Anticoagulants
Vaccines
1.Pre-clinical development - in vitro and in vivo(animal models) testing research carried out
in lab assays and on animals.
2.Clinical development

Scope Nr subjects
Phase I Safety 20 healthy volunteers
Imunogenicity (10 – 100)
Phase II Imunogenicity 100-1000
(seroconversion)– (randomisation, control)
dose and interval
Safety
Efficacy
Phase III 1000-10 000
efficacy under natural large scale across several sites
disease conditions Heterogeneous population

Licensing
Post-marketing surveillance,
-detect rare adverse effects
assess long term efficacy.
- Inactivated Vaccins, 2 doses 0-14 days
- 3 in China
• Sinovac
• Wuhan Institute of Biological Products/ Sinopharm
• Beijing Institute of Biological Products/ Sinopharm)

- New platforms for immunogens expresion- protein S (spike)

mRNA - deliver the RNA of interest (for protein S)
• Moderna 2 doses , 0, 28 days
• BioNTech/Pfizer 2 doses , 0,28 days

Adenoviral Vectors / Replication deficient

Ad5 - CanSino Biologics/Beijing Institute of Biotchenology, China 1/ 2 doses
ChAdOx1- AstraZeneca/University Oxford/ - 1/ 2 doses
Ad26-COVS1-Jansen Pharmaceutical Companies- 2 doses 0, 56 days
rAd26-S +rAd5-S-Gamaleya Research Institute- 2 doses – 0, 21 days

Nanoparticles containing recombinant S proteins, Novavax- SARS CoV2 - Matrix, 2 doses

0, 21 days
EBOLA VIRUS
VIRAL HEMORRHAGIC FEVER

2014-2015- West Africa

>28 000 cases; >11 000 deaths

2019 – DRC
1818 cases
1277 deaths - 70% lethality rate
•FILOVIRIDAE ("filo" – filamentous infectious viral particles (-) ss RNA
nonsegmented;
•80 nm diameter and high length (Ebola-970nm, Marburg-790nm); envelope,
– High resistence in aerosols, easily respiratory transmitted
– The most lethal agents known to man
Ebola: mortality of 88% (in some outbreaks) - by comparison, mortality of
pneumonic plague: 40-70% / Marburg: 25%

Marburg
Ebola
Natural host probable - bats
Rata mortalitatii
25 -90%
Ebola Virus - GP EBOV- target immunogenic antigen

GP
Essential role in attachment
Neutralising antibodies
 Two viral platforms for EBOV
harmless version of viruses

• Replication competent Virus :

Vesicular stomatitis virus (rVSV)

• Replication deficient Virus :

Human recombinant adenovirus
(rAd) or Chimpanzee adenoviral
vectors

Ervebo R (MSD) - rVSV-G-EBOV-GP

 Ervebo
Recombinant vesicular stomatitis
virus–Ebola virus (Zaire strain)
(rVSV-ZEBOV Ebola vaccine)
'ring vaccination' strategy - the contacts of
confirmed cases, and the contacts of contacts

Ebola Epidemic (DRC Kivu)- 2018-2020- 290 000

vaccinated persons -Efficient in 97.5%