Immunisation against Respiratory Syncytial Virus (RSV) In New Zealand - Dr Adrian Trenholme Paediatrician October 2020 - Amazon ...
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Immunisation against Respiratory
Syncytial Virus (RSV)
In New Zealand
Dr Adrian Trenholme
Paediatrician
October 2020
Koira4Rukahukahu
Vale Dinny
RSV
• Background
– Virus
– Global
– NZ
• Prevention
• Treatment
• Immunisation current status and results
• 2020 update
RSV
RSV illness
Openshaw
Openshaw PJM; Chiu C; Culley FJ; Johansson C. Protective and Harmful Immunity to RSV Infection. Annual Review of Immunology. 35:501-532, 2017 Apr 26
RSV Worldwide 65y US Falsey 2005 NEJM
4-7% /y
10% of admissions with cardiopulmonary diagnosis.
RSV Local data sources
• South Auckland
– 2002-2005 Trenholme PSNZ 2007
– 2009-11 Trenholme A. J Paediatr Child Health. 2017 Jun;53(6):551-555
– 2010-14 Trenholme Paed Pulmonology
– 2020 Byrnes C Trenholme A Healthy Lungs Study Thorax
• University of Otago Epidemiology reports NMDS
http://www.otago.ac.nz/nzcyes/reports-by-category/
• SHIVERS PROJECT 2012-2016
• Huang S West Pac Surveill Response J. 2014 May 20;5(2):23-30
• Prasad N RSV burden children EID 2019, EC burden
LRI Admissions < 2 years 2002-2006 CMH Kidz First
400
350
300
250
200
LRI by month and 150
diagnosis 100
50
0
Ma 2
2
2
2
Ma 3
3
3
3
4
4
4
Ja 4
Ma 5
5
5
5
Ma 6
6
Se 6
6
Ma 2
Ma 3
Ma 4
Ma 5
Ma 6
2
3
4
5
6
n-0
y-0
l-0
v-0
n-0
y-0
l-0
v-0
n-0
y-0
l-0
v-0
n-0
y-0
l-0
v-0
n-0
y-0
l-0
v-0
r-0
r-0
r-0
r-0
r-0
p-0
p-0
p-0
p-0
p-0
Ju
Ju
Ju
Ju
Ju
No
No
No
No
No
Ja
Ja
Ja
Ma
Ja
Se
Se
Se
Se
Whooping cough Bronchiolits Pneumonia Bronchiectasis Other LRI Grand Total
Broncholitis
600
500
Bronchiolitis
400
admission by age
300
200
100
0
Age 2 4 6 8 10 12 14 16 18 20 22 24
other Maori Pacific Islander Grand Total
Trenholme A- PSNZ 2007
NMDS LRI Admission rates < 1 year of age,
Birth cohort CMH 2012-13 by ethnicity and
socioeconomic statusRSV Burden 2013-18
Influenza and RSV Incidence by age 2012-15 Huang S SHIVERS 2015
ChildrenRSV Long term problems
• Death- NZ 2 deaths per year from bronchiolitis (NZCYES 2000-2008)
• Recurrent wheezing – 50% Stein Lancet. 1999 Aug 14;354(9178):541-5
• Asthma
– 39% vs 9% Sigurs, N.- Thorax. 2010 Dec;65(12):1045-52. doi: 10.1136/thx.2009.121582
• Non-Cystic Fibrosis Bronchiectasis –
– 3-7% (Trenholme Paed Pulmonology Volume 48, Issue 8 August 2013 Pages 772–779 )
– 13/18 Bx with RSV
• Vitamin D?? 33% LRIHow to tackle RSV in NZ • Environment-Housing/Poverty • Treatment • Prevention – Immunoprophylaxis-monoclonal antibodies – Immunisation-first started in the 1960,s
Treatment • Ribavirin –nucleoside analogue • Cytosine analogues- – RSV RNA Polymerase inhibitor Lumicatabine/ALS-008176 • Viral replication- – Nitazoxanide • Fusion blockers- – Presatovir, GS-5806, AK0529, JNJ-53718678
Prevention Immunoprophylaxis-
Monoclonal Antibodies
• Palivizumab/Motavizumab A.Vogel- J Pediatr Child Health 2002 Dec;38(6):550-4
– Monthly injections x5 $$$
– 50% reduction hospitalisation
– Exceptional circumstances
• ALX 0171 Inhaled nanobody
• REGN2222 Development halted Innefective –NURSERY Trial
• Long acting MEDI8897
– One IM per seasonRSV Immunisation
• 1968 Formalin Inactivated vaccine-enhanced disease for RSV naïve
80% hospital, 2 deaths
Lack of neutralising bodies
Th2 response
Immune complexes and
lack of Treg
• WHO-great caution in RSV naïve/non replicating
• Live attenuated
• Sub unit/particle
• Gene based vectors
Kim et al. Am J. Epi. 1968;89,4:422-434Novavax PREPARE
• A Phase 3, Randomized, Observer-Blind, Placebo-Controlled, Group-Sequential
Study to Determine
– 1-the Immunogenicity and Safety of a Respiratory Syncytial Virus (RSV) F Nanoparticle
Vaccine With Aluminum in Healthy Third-trimester Pregnant Women; and
– 2-Safety and Efficacy of Maternally Transferred Antibodies in Preventing RSV Disease in
Their Infants
• Virus F nanoparticle with Aluminium adjuvant
• Neutralising and Paluvimazib competing Antibodies.
• Very healthy women for safety (low risk RSV)
• 280 to 360 weeks gestation immunisation
• 2016-2019
• 236 women in NZ
• 4636 women worldwide (over 8000 planned)
• Auckland Christchurch Wellington
• Gates Foundation funding
• NCT02624947A RSV-M-301
• August A. Vaccine Volume 35, Issue 30,
• 27 June 2017, Pages 3749-3759Primary Endpoint
Medically Significant RSV LRTI
(MSLRTI) to day 90
– the presence of RSV infection
– AND at least one manifestation of LRTI
• cough, nasal flaring, lower chest wall indrawing, subcostal
retractions, stridor, rales, rhonchi, wheezing,
crackles/crepitations, or observed apnea;
– AND evidence of medical significance –hypoxia or tachypnoea
• EITHER hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea
level
• OR tachypnea (≥ 70 breaths per minute [bpm] in infants 0 to 59 days of
age and ≥ 60 bpm in infants ≥ 60 days of age, observed by study staff).
» Lab data –central lab only
» Clinical data study team assessed only
» Per protocol excludes prem etcSecondary Endpoints • RSV LRTI with severe hypoxia sats
Populations studied • Per Protocol excludes prems etc • Intention to treat includes all with any efficacy data • Expanded dataset-includes data obtained by non study sites/teams
Randomization and Conduct
• Enrolment of up to 8,618 pregnant women was planned based on
– a presumptive primary endpoint attack rate of 4%
– efficacy of ~60%.
– Slow enrolment first season-informational analysis after 2 years VE >40%
– Minimum safety data on 3000 active vaccine recipients
– Total 4636 enrolled and randomised
• Randomization was at site level, and stratified by age (18 to < 29, 29 to 40
years).
• Women were randomized
– 1:1 to vaccine (120 μg RSV-F protein adsorbed to 0.4 mg aluminium) or
placebo (formulation buffer) in the first global RSV season.
– 2:1 thereafter.Analysis
• Primary and secondary VE analyses were based on the Per-
Protocol population (PP), from observations by trained site
staff
• VE against the primary endpoint, RSV-MS-LRTI through 0-90
days of age
– one-sided Type I error rate of 0.0124 (i.e., lower bound of a two-sided
97.52% CI).
– Success in the primary objective required exclusion of VEVaccine Efficacy
Intention to treat population efficacy analysis of RSV nanoparticle F-protein against respiratory syncytial virus (RSV) and all-cause-associated lower respiratory tract infections in infants born to pregnant women vaccinated with RSV F vaccine or placebo, by low-middle and high income countries.
Summary • RSV associated MSLRTI VE 40% did not meet FDA primary endpoint • Safe for mothers and infants • Immunogenic with good infant transfer • Trial methodology – rare endpoints in healthy – stopped early – missed endpoints – Different in HIC vs M/LIC • RSV endpoints-lots of learning
Signals • More effective in MIC/LIC especially African population • Effective for – RSV ---severe hypoxia and hospitalisation to day 90 – All cause LRTI ---severe hypoxia and hospitalisation to day 90 • Non specific effect on – all cause LRTI---- hospitalisation to d180 – AE Pneumonia ----to d180 and d360 • Await full analysis of neutralising antibodies for ? immune correlate of protection
Then • COVID 19 lockdown March 2020 and non pharmaceutical interventions (NPI) thereafter • Hospitalisations dropped below summer levels • July 2020-we were not seeing RSV or Influenza • UK, Finland and Alaska rapid fall in RSV and Influenza with COVID 19 NPI at end of winter season – Nolen L CID 2020, Kuitenen L PIDJ 2020, Iacabucci G BMJ 2020 • Australia report fall in RSV and Influenza over winter – Britton P Lancet Child and Adolescent Health 2020
RSV 2020 Trenholme/Webb
Kidz First
• Kidz First hospital data only
• Clinical and laboratory records of infants less than 2 years
of age hospitalised with LRTI for >3 hours between 1st
January 2015 and 31st August 2020 for LRTI (ICD-10 codes
J22, A37, J47, J10.0 J10.1 J11.1, J12-16 J20, J21, J18) were
reviewed.
• All clinician-directed specimens submitted for respiratory
viral PCR testing were identified for the same time period.
Re-admissions and duplicate tests were not excluded from
this dataset. SHIVERS screening not included.Respiratory LRTI hospitalisation>3h for infants
Children under two years of age admitted with LRTI
March 1st to August 31st from 2015 to 2020
Respiratory virus PCR test numbers,
Total hospitalisations
Hospitalisations associated with positive respiratory viral PCR tests
2015 2016 . 2017 2018 2019 2020
LRTI Hospitalisation 1249 881 1012 916 1031 159
Virus PCR tests total 7259 6642 8876 7676 14881 6735
RSV PCR +ve Hospitalisation n 214 224 317 204 388 2
Influenza A PCR +ve Hospitalisation n 28 16 56 53 85 1
Influenza B PCR +ve Hospitalisation n 11 6 11 1 97 0
RV/EV PCR +ve Hospitalisation n 285 274 378 283 495 252
Adenovirus PCR +ve Hospitalisation n 106 26 83 66 72 41Children under two years of age admitted with LRTI
Respiratory Virus tests Mar 1 to July 31 2015 to 2020
.
PIV 1=0
PIV 4=0
PIV 2 =2
Pertussis=0 Sharon Arrol Oct 2020Children under two years of age admitted with LRTI
March 1st to August 31st from 2015 to 2020
Enterovirus/Rhinovirus positive tests
+ve results for Jan - Sept 20
120
100
80
60
40
20
0
Jan-20 Feb-20 Mar-20 Apr-20 May-20 Jun-20 Jul-20 Aug-20 Sep-20
Rhinovirus/Enterovirus Adenovirus Types 1-8 Influenza A Respiratory Syncytial Virus
Sharon Arrol Oct 2020Summary-Impact of NPI for COVID 19 • Absence of seasonal winter virus burden – RSV – Influenza – HMPV – ?PIV • Relatively unchanged burden overall for Rhinovirus and Adenovirus but reduced in strict lockdown • No Covid 19 hospitalisations
RSV 2020 Study Trenholme/Webb
Conclusion
• Border controls prevent import and spread of seasonal
viruses
• Endemic respiratory viruses still cause a disease burden
in infants despite the various NPI measures used
• Maaori and Pacific infants have short and long term
respiratory benefits from NPI for COVID 19
• The biggest respiratory virus experimental study ever?
• 2021 and beyond?
– can we do RSV vaccine/immunoprophylaxis research nowRSV modelling
• Modelling the impact of respiratory syncytial
virus (RSV) vaccine and immunoprophylaxis
strategies in New Zealand Namrata Prasad
• Developed a Mathematical model of RSV
transmission based on Auckland data to
– describe seasonal epidemics and
– assess the impact of potential vaccines and
monoclonal antibodiesRSV modelling
RSV Modelling
• The model accurately reproduced the annual seasonality of RSV epidemics
in Auckland.
• A maternal vaccine with effectiveness of 40–50% in the first 90 days and
20–30% for the next 90 days would reduce RSV hospitalisations by
– 31–40% in children younger than 3 months,
– 23–33% in children aged 3–5 months, and by
– 15–20% in children aged 6–23 months.
• A seasonal infant mAb with 50–70% effectiveness for 150 days would
reduce RSV hospitalisations by
– 48–62% in children younger than 3 months
– 53–67% in children 3-5 months and
– 38–50% in children aged 6–23 monthsSo-RSV Immunisation-Current • First study done showing RSV maternal Immunisation is safe and has limited effectiveness-in further trials but unlikely to be commercially available in NZ ?NZ trials in high risk • More Immunogenic Prefusion RSV maternal vaccines in phase 3 currently in NZ-years away from production • Live vaccine and virus vector vaccines in phase 2 • Once per season mAb effective in phase 2 and now in phase 3 in NZ for Prems and Term babies—may work but may be too expensive like Palivizumab
But • RSV in infants did not happen 2020 • Can this be sustained? • Are vaccine/monoclonal studies going to continue ? • If RSV returns would a combined maternal/infant vaccine or monoclonal for high risk strategy be cost effective (Prasad 2020)
Discussion • Importance of RSV for short/long term infant health • NZ participation in commercial vaccine trials • Importance of surveillance as shown by COVID 19-link with WHO programmes • ?Border testing for RSV /Influenza 2021on
APRILIA RSV MILLE
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