Anna Durbin, MD Professor of Medicine & Public Health Kawsar - - PowerPoint PPT Presentation

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Anna Durbin, MD Professor of Medicine & Public Health Kawsar - - PowerPoint PPT Presentation

Jul 09, 2023 46 likes •538 views

Anna Durbin, MD Professor of Medicine & Public Health Kawsar Talaat, MD Assistant Professor of Medicine & Public Health Johns Hopkins Vaccine Initiative, Center for Immunization Research Drs. Chida, Durbin, Melia, and Talaat have no

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Anna Durbin, MD Professor of Medicine & Public Health Kawsar Talaat, MD Assistant Professor of Medicine & Public Health Johns Hopkins Vaccine Initiative, Center for Immunization Research

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  • Drs. Chida, Durbin, Melia, and Talaat have no relevant disclosures
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Clinical Case

  • 18 year old female who presented 2 day

history of high fever (39 – 40.2), severe headache, abdominal pain, and rash.

  • Rash was located on distal upper and lower

extremities and was petechial

  • Pneumonia evident on CXR
  • Found to have atypical measles
  • Had been vaccinated as a child with 3 doses of

formalin inactivated measles vaccine

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Atypical measles

  • Occurred years after initial vaccination

with formalin inactivated measles vaccine

  • 3 doses given 1 month apart
  • Rash began on the distal extremities

and concentrated on the ankles, wrists, and creases

  • High fever, severe headache, severe

abdominal pain, often vomiting

  • 15 – 60% of immunized children

subsequently exposed to wild-type measles virus developed atypical measles

Temperature Age Sex MAX. Duration (days) Rash Edema Pneum

  • nia

6 F 40.6 7 M,V,P + RML 6 M 39.4 7 M,P + ? 7 F 40.0 7 M,V,P + B+E 7 F 40.6 7 M,P + RLL+E 6 M 40.0 5 M,P B 6 F 40.0 5 M,V,P + RML 8 F 40.6 4 M RML 6 M 40.6 6 M,P B+E 7 F 39.4 4 M,V + RLL 8 F 40.6 5 M + RLL

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Immune pathogenesis

  • Immune enhancement of disease has been documented with formalin

inactivated measles and RSV vaccines.

  • The vaccines induced antibodies however the protection was transient
  • Secondary exposure to wildtype measles led to a CD4 response with a Th2

bias

  • Eosinophilic and neutrophilic infiltrates found in the lungs
  • Immune complex deposition in the lungs
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Why We Need a SARS-Cov-2 Vaccine

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Where Things Stand with Herd Immunity

https://www.nytimes.com/interactive/2020/05/28/upshot/coronavirus-herd- immunity.html?action=click&module=Well&pgtype=Homepage&section=The%20Upshot. Accessed 29 May 2020.

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Lessons from 1918 Influenza Pandemic

  • Study of weekly pneumonia and influenza mortality data for 43 US

cities.

  • 1920, combined population of approximately 22% of the total US population
  • Nonpharmaceutical interventions grouped into 3 major categories:

school closure; public gathering bans; and isolation and quarantine

Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

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Timing

Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

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Length of Intervention

Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

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Length of Intervention

Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

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Lessons from 1918 Influenza Pandemic

  • Cities implementing multiple interventions early → peak death rates

~50% lower than those that did not

  • Death rates climbed after interventions were lifted
  • For these “second waves:” inverse correlation of height of first and

second peak weekly mortality rates

  • Cities with low first wave peaks at greater risk of large second wave
  • These low first wave peak cities experienced second waves sooner
  • ~6-8w after the first peak vs. 10-14w for cities with higher first peak mortality rates
  • No city experienced a second wave with main NPI battery in place

Hatchett RJ et al. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7582-7.

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Lessons from 1918 Influenza Pandemic

Hatchett RJ et al. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7582-7.

City 1918 Death Rate CEPID at school closure CEPID at 4th Intervention Height of Peak 1 Height of Peak 2 Weeks between P1 and P2

Baltimore 601.87 54.31 54.31 215.71 13.60 14.00 Boston 623.13 96.25 125.60 162.23 27.23 13.00 Cincinnatti 430.63 2.09 4.64 68.33 48.63 7.00 Cleveland 428.10 15.08 12.36 87.63 28.15 7.00 Indianapolis 264.75 16.88 16.88 40.63 30.33 6.00 Kansas City 531.23 25.68 5.55 61.23 76.19 6.00 New Orleans 573.27 24.73 29.85 177.27 46.42 12.00 Pittsburgh 647.60 158.43 10.34 132.63 20.90 14.00

  • St. Louis

346.50 6.23 7.58 31.29 57.46 6.00

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Immunology & Vaccines

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CoV immunoprotective vs immunopathogenic immune response

  • Antibody enhancement of infection
  • Feline enteric CoV (FECV) causes mild
  • r asymptomatic infection
  • Macrophage tropic variant is feline

intestinal peritonitis virus (FIPV)

  • Antibody to FECV does not protect

against FIPV

  • Enhanced disease seen in animals

passively or actively immunized against FIPV but not in those naturally infected

  • ADE of infection has not been

demonstrated in vivo with SARS- CoV vaccines

Perlman, Nat Rev Immun 2005

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Antibody enhanced disease with SARS-CoV vaccines

  • Recombinant vaccinia virus (VV) expressed the SARS-CoV S protein or

VV expressing all the structural proteins (N, M, E, and S) of SARS-CoV

  • Mice immunized with the

VV-NMES vaccine developed as severe pneumonia post-SARS-CoV challenge as placebo recipients even though titers of SARS- CoV were reduced to the same extent as the VV-S vaccine

  • Pathology was not due to vaccine titers
  • Evaluated

VV expressing individual structural proteins

  • VV-NS vaccinated mice developed anti-N antibodies (non-neutralizing) and anti-S

(neutralizing)

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Immunopathology of VV expressing N

  • SARS-CoV vaccine expressing the N

protein (VV-N) induced pathology in the lungs of mice following challenge

  • Immune response induced by the

vaccine was a Th2 bias (IL-4, IL-5, and IL- 10) and high expression of IL-6

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Inactivated SARS-CoV vaccines

  • Wild-type SARS-CoV inactivated with formalin and UV, doubly inactivated

(DI) & a beta propiolactone-inactivated vaccine (BPV)

  • These were tested in mice prior to clinical trial use
  • Compared with a DNA spike protein vaccine
  • T

ested alone and adjuvanted with alum (achieved higher Ab titers)

  • Evaluated immunogenicity and protective efficacy of the vaccine in young

and senescent mice

  • Challenged with both homologous and heterologous CoV challenge
  • The vaccine provided protection to young mice but did not provide protection

against challenge in old

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Eosinophilic infiltration of lungs of mice following DIV SARS-CoV vaccine & challenge

  • DIV vaccine adjuvanted with alum did not

provide protection against homologous and heterologous challenge in aged mice

  • Both DIV and DIV plus alum vaccines caused

enhanced immune pathology in the lungs compared to placebo recipients

  • Immunopathology occurred in the absence of

virus in the lungs

  • BPV & S DNA vaccines less pathogenic
  • Cytokine profiles demonstrated Th-2 skewed

response

Tseng, PLoS ONE, 2012

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DIV vaccination predisposes to enhanced lung pathology

Bolles et al J of Virol 2011

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What did we learn?

  • Inactivated SARS-CoV vaccine using formalin and UV irradiation (double-

inactivation) as well as BPV protected against SARS pneumonitis but caused immunopathology in the lungs post-challenge in younger mice

  • Immunized year-old mice (to represent older population)
  • Assessed homologous and heterologous challenge in mice
  • Vaccine induced antibodies against S protein and N protein. Antibody titers with Alum

adjuvant compared to PBS or VAP adjuvant

  • Vaccine induced incomplete completion: DIV alone did not significantly reduce titers in the

lungs, DIV+ alum reduced titers but to lesser extent in elderly mice

  • The alum-adjuvanted DIV induced a strong skew in the N- and S-specific antibodies toward

IgG1, a subtype associated with Th2 immune responses

  • Immune pathology was demonstrated following vaccination with the SARS N

protein

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SARS-CoV-2 immunoprotective vs immunopathogenic immune response

  • Antibody dependent enhancement of disease was observed with SARS-CoV

vaccines

  • Key to protection against SARS-CoV is the development of neutralizing

antibody

  • SARS-CoV neutralizing antibodies are sufficient to provide complete

immunity against lethal SARS challenges in multiple animal models

  • Appears to be true for SARS-CoV-2
  • High enough neutralizing antibody was able to abrogate immunopathology
  • Vaccines must demonstrate they do not skew to Th2 response in pre-clinical

and clinical studies

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Protective immune response

  • SARS-CoV neutralizing antibodies are sufficient to provide complete

immunity against lethal SARS challenges in multiple animal models

  • Appears to be true for SARS-CoV-2
  • The N protein is highly immunogenic but does not induce protection and

appear to affect the longevity of protective antibodies.

  • The immune response to the N protein induces immunopathology when it is given

along

  • Induction of enough neutralizing antibodies can protect against SARS-CoV

vaccine induced immunopathology

  • How to induce these antibodies?
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Protective immune response

  • Coronaviruses posses trimeric Spike proteins required for host receptor

recognition, binding, and viral entry into cells

  • The S1 subunit binds host receptors (RBD); the S2 subunit is responsible for

membrane fusion

  • The pre-fusion S protein exists in a meta-stable state: the receptor-binding

site on the S1 RBD is occluded when the RBD is in the “in” conformation

Pallesen, PNAS, 2017

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SARS-CoV-2 vaccine immunogenicity

  • Most potent neutralizing antibodies are those that target the pre-fusion

state of S

  • Early vaccine candidates were unable to generate high titers against

prefusion S because S protein prefusion state is not stable

  • Newer candidates have used recombinant DNA technology to introduce

stabilizing mutations into S for SARS, MERS, and SARS-CoV-2

  • Can express recombinant S protein in the pre-fusion state
  • These vaccines should induce high titers of strongly neutralizing antibody
  • Pre-clinical studies of some of these candidates have demonstrated Th1 response
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SARS-CoV-2 Vaccine Pipeline

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Vaccine Safety

  • Of paramount importance to any vaccine given to healthy people
  • All studies evaluating novel vaccines will have safety as a primary outcome
  • FDA monitors pre-licensure safety of candidate vaccines- it will only license

a vaccine if it is safe and effective

  • Both the FDA and the CDC monitor post-licensure safety of vaccines
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https://www.cdc.gov/vaccines/parents/infographics/journey-of-child-vaccine.html

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Vaccine Development in a Pandemic

  • Normal timeline 10-30

years

  • Fastest vaccine to be

developed 4 years

  • Goal to speed it up to 12-

18 months

  • Overlapping phases

https://www.nytimes.com/interactive/2020/04/30/opinion/coronavirus- covid-vaccine.html?referringSource=articleShare Lurie, N. et al. NEJM 2020 March 30, 2020 DOI: 10.1056/NEJMp2005630

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  • Potential

Vaccine Platforms

  • 152 vaccines currently in

development

  • 10 in clinical trials
  • 8 in Phase 1
  • 2 in Phase 2

Nature: The race for coronavirus vaccines: a graphical guide by Ewen Callaway https://www.nature.com/articles/d41586-020-01221-y Nature 580, 576-577 (2020)doi: 10.1038/d41586-020-01221-y https://milkeninstitute.org/covid-19-tracker

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CEPI- Coalition for Epidemic Preparedness Innovations

  • A global alliance financing and coordinating the development of vaccines

against emerging infectious diseases

  • Launched 2017
  • Mission: to accelerate the development of vaccines against emerging

infectious diseases

  • To enable equitable access to these vaccines during outbreaks
  • Fund innovative vaccines and technologies
  • Platforms that allow switching of viruses into established technologies
  • Mechanisms that speed up R&D and manufacturing
  • Commitment to provide vaccines for the world
  • Funded 4 of the vaccines in clinical trials
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  • No current licensed vaccine uses

this technology

  • Very fast to create
  • First vaccines to go into clinical

trials

  • Moderna mRNA vaccine
  • Phase 1 started March 2020
  • BioNTech and Pfizer- mRNA
  • Phase 1 Germany and US
  • Inovio = DNA vaccine
  • Phase 1 underway

https://blogs.sciencemag.org/pipeline/archives/2020/04/23/a-close-look-at-the-frontrunning- coronavirus-vaccines-as-of-april-23 The race for coronavirus vaccines: a graphical guide by Ewen Callaway https://www.nature.com/articles/d41586-020-01221-y Nature 580, 576-577 (2020) doi: 10.1038/d41586-020-01221-y

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Moderna mRNA vaccine (mRNA-1273)

  • Platform developed with CEPI funding
  • Vaccine developed in partnership with Vaccine Research Center, NIH
  • Phase 1 Open Label dose ranging study started March 2020
  • Given at 25, 100 and 250 microgram 18-55 yo (15 /cohort)
  • Added 10 and 50 ug arms (expanded age to all adults)
  • Press Release May 18
  • Preliminary Phase 1 information
  • No actual data shown
  • Phase 2 started May 29
  • 50 and 100 ug, placebo controlled in adults 18 and older

Source: https://www.nytimes.com/interactive/2020/05/20/ science/coronavirus-vaccine-development.html

https://investors.modernatx.com/news-releases/news-release-details/moderna-announces- positive-interim-phase-1-data-its-mrna-vaccine

Phase 1: ClinicalTrials.gov Identifier: NCT04283461 Phase 2: ClinicalTrials.gov Identifier: NCT04405076

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Moderna mRNA-1273 Immunogenicity

  • Dose dependent increase in immunogenicity
  • Increase in immune response after second dose of the 25 and 100 ug doses
  • All seroconverted after a single dose
  • 2 doses of 25 ug (n=15) gives equivalent binding antibodies to

convalescent serum

  • 2 doses of 100 ug (n=10) binding antibody exceeds convalescent titers
  • Only have neutralizing titers for 4 volunteers each from 25 ug and 100 ug
  • Plaque Reduction Neutralization (PRNT) assay- levels of antibodies at day

43 “at or above levels generally seen in convalescent sera”

https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive- interim-phase-1-data-its-mrna-vaccine

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Moderna mRNA-1273 safety

  • 3 subjects in 250 ug dose with Grade 3 (severe) systemic illness after 2nd

dose

  • 1 subject in 100 ug dose with Grade 3 erythema at injection site
  • All adverse events noted to be “transient and self resolving”
  • No Serious Adverse Events reported
  • FDA gave approval for Phase 2
  • Granted Fast Track designation by FDA

https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim- phase-1-data-its-mrna-vaccine https://investors.modernatx.com/news-releases/news-release-details/moderna- announces-first-participants-each-age-cohort-dosed-phase

Phase 1: ClinicalTrials.gov Identifier: NCT04283461

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BioNT ech-Pfizer mRNA vaccine BNT162

  • Developed by BioNTech licensed by Pfizer
  • Evaluating 4 different SARS-CoV-2 RNA vaccine candidates
  • 2 nucleoside modified RNA vaccines
  • Uridine containing mRNA vaccine
  • Self-amplifying mRNA
  • 3 doses/vaccine 2 age cohorts 18-55 and 65-80
  • Phase 1/2 placebo control study evaluating each vaccine at 3 different doses

started May 2020

  • 1st stage will enroll 360 volunteers
  • Production of vaccine starting- producing vaccine at risk

https://www.pfizer.com/news/press-release/press-release- detail/pfizer_and_biontech_dose_first_participants_in_the_u_s_as_part_of_global_covid_19_mrna_vaccine_develop ment_program http://www.pmlive.com/pharma_news/us_trials_of_pfizerbiontech_coronavirus_vaccine_start_1339865

ClinicalTrials.gov Identifier: NCT04368728 (US) ClinicalTrials.gov Identifier: NCT04380701 (Germany)

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DNA Vaccine- Inovio INO-4800

  • CEPI funded
  • DNA vaccine, administered with electroporator (Cellectra 2000)
  • Open label Phase 1 trial started April 2020 in adults age 18-50 years
  • 1 vs 2 mg ID followed by electroporation
  • Non-replicating, non-integrating DNA
  • DNA is transcribed into protein
  • Neutralizing Antibodies and CD8 responses
  • MERS vaccine using same platform
  • Phase 1 dose escalating open label study
  • 75 volunteers enrolled received 3 doses of vaccine
  • Well tolerated, immunogenic with seroconversion 94% but neutralizing antibodies in 50%. T cell

responses in 76%.

ClinicalTrials.gov Identifier: NCT04336410

Modjadarrad Lancet ID 2019 INOVIO_Investor_Presentation_April_2020.pdf

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  • Currently licensed vaccines:
  • Ebola vaccine
  • Dengue vaccine
  • Leading candidates in trials
  • CanSino (Adenovirus 5)
  • Oxford vaccine (Chimpanzee

adenovirus)

  • Effective in nonhuman

primates

  • Phase 1 April 2020
  • Johnson and Johnson (Janssen)
  • Adenovirus vectored
  • Phase 1 in September

The race for coronavirus vaccines: a graphical guide by Ewen Callaway https://www.nature.com/articles/d41586-020- 01221-y Nature 580, 576-577 (2020) doi: 10.1038/d41586-020-01221-y

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CanSino Ad5 Vectored Vaccine

  • Replication defective Adenovirus 5 virus vector expressing an optimized spike glycoprotein

gene

  • Phase 1 open label, dose ranging trial done in Wuhan, China in 18-60 year olds
  • 5 x 1010, 1 x 1011, 1.5 x 1011 viral particles given intramuscularly (n=36/group)
  • single dose
  • Limitation: human adenovirus vector- widespread pre-existing immunity

Zhu Lancet 2020 https://doi.org/10.1016/ S0140-6736(20)31208-3 Phase 2: ClinicalTrials.gov Identifier: NCT04341389

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Immunogenicity of CanSino Ad5 vaccine

CD8+ T cells, Day 14 CD4+ T cells, Day 14

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https://covid19vaccinetrial.co.uk/about

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ChAdOx1 nCoV-19

  • Developed by Jenner Institute and Oxford Vaccine Group
  • Platform received CEPI funding
  • Licensed by AstraZeneca (now AZD 1222)
  • Replication deficient chimpanzee adenoviral vector coding for SARS CoV-2

spike protein

  • Nonreplicating
  • Platform used in other vaccines in >320 people previously
  • Side effects: Fever, influenza like-illness, headache, sore arm
  • Phase 1 trial in >1,000 healthy adults 18-55 in UK

Source: https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/astrazeneca-advances- response-to-global-covid-19-challenge-as-it-receives-first-commitments-for-oxfords-potential-new-vaccine.html https://www.nytimes.com/2020/05/21/health/coronavirus-vaccine-astrazeneca.html http://www.ox.ac.uk/news/2020-05-22-oxford-covid-19-vaccine-begin-phase-iiiii-human-trials

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ChAdOx1 nCoV-19 Phase 1 trial

Dose : 5x1010 viral particles

https://covid19vaccinetrial.co.uk/phase-i-trial-explained ClinicalTrials.gov Identifier: NCT04324606

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AstraZeneca Oxford vaccine- AZD 1222

  • Received up to 1.2 billion from BARDA for development of vaccine
  • Has “secured” manufacturing capacity for 1 billion doses through 2020 and

“into 2021”

  • Phase 2/3 trial in UK expands age, numbers up to 1,260
  • 30,000 participant Phase 3 trial planned in US
  • Pediatric trial
  • Partnering with CEPI, Gavi, WHO for fair allocation of vaccine

ClinicalTrials.gov Identifier: NCT04400838

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  • Licensed protein subunit vaccines:
  • Influenza, many others
  • Investigational coronavirus vaccines (many)
  • Novavax Phase 1/2 start May 2020
  • Clover Biopharmaceuticals Inc. + GSK Adjuvant, Dynavax
  • Phase 1 June 20, 2020
  • Licensed

Virus like particle vaccines:

  • Human papillomavirus
  • Investigational coronavirus vaccine
  • Medicago (phase 1 July/August 2020)

The race for coronavirus vaccines: a graphical guide by Ewen Callaway https://www.nature.com/articles/d41586-020- 01221-y Nature 580, 576-577 (2020) doi: 10.1038/d41586-020-01221-y

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Novavax: NVAX-CoV2373

  • Stable pre-fusion recombinant spike protein nanoparticle vaccine
  • Funding from CEPI through Phase 2
  • Phase 1 trial started May 25 in Australia- 130 adults age 18-59
  • 2 doses 5 ug and 25 ug with and without adjuvant (Matrix M)

ClinicalTrials.gov Identifier: NCT04368988 http://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-12-clinical-trial-covid-19-vaccine https://cepi.net/news_cepi/cepi-extends-collaboration-with-novavax-to-advance-development-and-manufacture-of-covid- 19-vaccine/

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Operation Warp Speed

  • US Government initiative to “accelerate the development,

manufacturing, and distribution of COVID-19 vaccines, therapeutics and diagnostics (medical countermeasures).”

  • Align protocols for safety and efficacy
  • 14 vaccines being evaluated
  • Will shorten to 8 candidates that will go through early clinical trials
  • Large scale randomized trials for safety and efficacy for 3 to 5

vaccine candidates

  • 30,000 person Phase 3 trial for each vaccine candidate
  • Non-clinical testing in parallel
  • Manufacturing at risk

https://www.hhs.gov/about/news/2020/05/15/trump-administration-announces-framework-and-leadership-for-operation-warp-speed.html Image:https://steamcommunity.com/sharedfiles/filedetails/?id=805008478

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https://marchforscience.org/keep-calm-and-flatten-the-curve/

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SLIDES & RECORDINGS ARCHIVED ONLINE

https://bit.ly/2Y2DIDj