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WHO Draft Rapid Response +
Containment, May 2006
Projected Outbreak of H5N1 in Thailand
R0 = 1.5
Red = new cases. Green = areas where the epidemic has finished.
Ferguson et al. Nature 437:209, 2005
Projected Outbreak of H5N1 Influenza in Thailand
Above: Controlled outbreak. Red = areas of
infection. Blue = areas where a combination of
control measures implemented.
Left: uncontrolled outbreak. Red = new cases.
Green = areas where the epidemic has finished.
http://www.nigms.nih.gov/news/releases/08032005.html
Elimination of a pandemic virus at its source?
• Ring chemoprophylaxis feasible if:
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–
–
–
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Geographically targeted in non-urban setting
Early intervention within 1-3 wks
Virus of low-moderate transmissibility (R0 < 1.8)
Chemoprophylaxis of 80 - 90% of population
High compliance
Movement restrictions; social distancing
• Maximum of 1-3 million courses needed
– 300,000 may be sufficient
Ferguson et al. Nature 437:209, 2005
Rapid Response: Antiviral Deployment
• Rapid use of antiviral prophylaxis is key component.
• Mass targeted antiviral prophylaxis:
– Goal of 90% coverage
– Geographic radius of 5-10 km from each detected case
OR
– Administrative area of “at-risk” population of 10-50,000
• Multiple logistical hurdles
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WHO donation of 3.0 M courses
440 courses = 7.8 kg
100,000 courses = 19 shipping pallets
Start dispensing within 12 hrs of receipt
WHO Draft Rapid Response + Containment Document, May 2006
Antiviral Resistance in Influenza Viruses
• M2 inhibitors:
– Primary resistance in epidemic (>90% of recent H3N2)
or pandemic virus possible; frequent with Rx
– Confers cross-resistance to entire class
– Resistant variants virulent and transmissible
• NA inhibitors:
– No primary resistance; active for all 9 NA types
– Inhibitory for M2 resistant-variants
– Variable NAI cross-resistance depending on
type/subtype and drug
– Most NAI resistance causes infectivity and virulence
in animals
NISN. Weekly Epi Record 33:306, 2004
Detection Of Antiviral Resistant
Influenza During Treatment
Frequency of resistance
Oseltamivir
M2 inhibitor
Out-patient adults
0.4%
~30%
Out-patient children
5.5%
~30%
Inpatient children
18%
80%
?
>33%
Immunocompromised
Roberts N. Phil Trans R Soc Lond 356:1895, 2001
Kiso et al. Lancet 364: 759, 2004
Pharyngeal Viral Loads during
Oseltamivir Treatment of H5N1
de Jong et al. NEJM 353:25, 2005
Neuraminidase Inhibitor Treatment : Antiviral
Resistance
• Emergence of oseltamivir-resistant variants may
be associated with prolonged viral detection in
A/H3N2-infected children and in H5N1-infected
patients.
– Resistance due to H274Y mutation may
compromise clinical efficacy in some H5N1
patients.
• No transmission of oseltamivir-resistant variants
detected in house-hold based studies or in
prophylaxis failures to date.
– Some resistant variants are transmissible in ferret
model (including H274Y mutation in N1)
Influenza Prevention In Households: PEP
Antiviral
(Study)
No.
Contacts
(age)
Oseltamivir
955
(Welliver et al, 2000)
(13+ yr)
Oseltamivir*
792
(Hayden et al, 2004)
(1+ yr)
Zanamivir*
837
(Hayden et al, 2000)
(5+ yr)
Zanamivir
1,291
(Monto et al, 2002)
(5+ yr)
*Index case given treatment
Reduction in
2° influenza
illness
Reduction in
influenza
infection
89%
49%
73%
35%
(Index +)
79%
62%
82%
59%
Interval from PEP Initiation to Secondary Illness
Onset in Household Contacts (N = 1,291)
Note: zanamivir PEP started < 36 hr of index illness onset
Monto et al. JID 186:1582, 2002
Influenza Post-exposure Prophylaxis (PEP)
with Neuraminidase Inhibitors: Summary
• Socially targeted antiviral prophylaxis (PEP) is
highly effective in protecting contacts in
households during seasonal influenza.
– Reductions in illness > infection.
– Secondary cases occur early, often in first few
days after index case recognition.
– Rapid initiation is essential.
• Inhaled zanamivir is also effective for prevention.
– Unstudied in human H5N1 infections to date.
Pandemic Vaccine Production
• Produce in existing facilities
• Produce with existing technologies
• Define the most antigen-sparing formulation for a
vaccine that will be acceptably immunogenic for a
population
– Develop formulation that can be used by all influenza
vaccine companies
• Goal is to make largest number of doses of an
affordable pandemic vaccine can be produced
worldwide.
• Immunologically naïve individuals will likely require
two doses of an adjuvanted, inactivated vaccine.
Fedson. J Public Health Policy 2005; 26:4-29
Dose Selection Considerations for Nonadjuvanted H5N1 Vaccine
g HA
per dose
% with Neut
titer  1:40
Number
Vaccinated
Number
protected
90
54
100
54
45
43
200
86
15
22
600
132
7.5
9
1200
108
Neuraminidase Inhibitor Prophylaxis
• Long-term prophylaxis (4-6 weeks) is highly
protective against seasonal influenza illness
(efficacy ~ 85-90%).
• Short-term prophylaxis (7-10 days) is protective
against influenza illness in household contacts
(efficacy ~ 70-90%).
• Protection is likely to be somewhat lower for
H5N1 or another novel strain.
• Illness will occur despite prophylaxis.
• If someone develops illness on prophylaxis,
increase dose to full therapeutic one.
Antivirals for H5N1: Conclusions
• Multiple potential reasons exist for treatment
failure, but viral clearance is associated with
favorable prognosis.
• Oseltamivir is preferred agent for treatment.
– http://www.who.int/csr/disease/avian_influenza/g
uidelines/pharmamanagement/en/index.html
– Appropriate dose regimen and duration for H5N1
are uncertain.
– Antiviral resistance with H274Y mutation may
compromise efficacy in some patients.
– No clinical data are available for inhaled
zanamivir at present.
Pharyngeal Viral Loads during
Oseltamivir Treatment of H5N1
de Jong et al. NEJM 353:25, 2005
Human Seasonal Vaccine
Only 300 million trivalent vaccine doses produced annually
from eggs for global market.
– Strains made available from WHO Global Surveillance Network
Production and consumption highly localized
– >95% produced in nine countries (>65% in Europe)
– 12% of population use 62% of vaccine
Production matches demand (i.e., market driven)
– Very little surge capacity, needs lead time of at least six months
– Increased seasonal demand enhances production capacity
Influenza pandemic vaccines
Lag between detection of
pandemic strain and full scale
vaccine production
– Optimistic approach
Clinical batch production and testing
1-2 month
Vaccine prototype development
1-2 month
Pandemic Vaccine Lessons from 1957,
1968, & 1977
• Unprimed subjects require 2 doses.
• Differences exist in immunogenicity between
subtypes.
• Whole virus is usually but not always more
immunogenic and reactogenic.
– Children have more side effects
• Adjuvants are useful and can spare antigen in
unprimed persons.
• Efficacy may be unpredictable.
Immunogenicity of Candidate H5N1
Vaccines in Healthy Adults
Vaccine type (N)
Route HA dose
% Neut
(µg)
titer > 1:40
Sub-virion, egggrown, nonadjuvanted X 2
(N=451)
Treanor et al. NEJM 354:1343, 2006
IM
7.5
15
45
90
9
22
43
54
H5 Vaccines: Summary
• Inactivated H5N1 vaccines are safe and
immunogenic.
– Reverse genetics enables rapid generation of
seed viruses with attenuated virulence.
• Unadjuvanted H5 appears to be a poor human
immunogen.
– Alum is somewhat effective as an adjuvant.
• Two doses of an adjuvanted H5 vaccine will
likely be required.
– Current capacity for 30 ug doses  250 M person
in 1st year