Anna Durbin, MD Professor of Medicine & Public Health Kawsar Talaat, MD Assistant Professor of Medicine & Public Health Johns Hopkins Vaccine ...
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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
Drs. Chida, Durbin, Melia, and Talaat have no relevant disclosures
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
Atypical measles Temperature
Duration Pneum
• Occurred years after initial vaccination Age Sex MAX. (days) Rash Edema onia
with formalin inactivated measles
vaccine 6 F 40.6 7 M,V,P + RML
• 3 doses given 1 month apart 6 M 39.4 7 M,P + ?
7 F 40.0 7 M,V,P + B+E
• Rash began on the distal extremities
and concentrated on the ankles, wrists, 7 F 40.6 7 M,P + RLL+E
and creases 6 M 40.0 5 M,P 0 B
• High fever, severe headache, severe 6 F 40.0 5 M,V,P + RML
abdominal pain, often vomiting 8 F 40.6 4 M 0 RML
• 15 – 60% of immunized children 6 M 40.6 6 M,P 0 B+E
subsequently exposed to wild-type 7 F 39.4 4 M,V + RLL
measles virus developed atypical 8 F 40.6 5 M + RLL
measles
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
Why We Need a SARS-Cov-2 Vaccine
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§ion=The%20Upshot. Accessed 29 May 2020.
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.
Timing
Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.
Length of
Intervention
Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.Length of
Intervention
Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.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.Lessons from 1918 Influenza Pandemic
Weeks
1918 Death CEPID at CEPID at 4th Height of Peak Height of Peak
City between P1 and
Rate school closure Intervention 1 2
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
Hatchett RJ et al. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7582-7.Immunology & Vaccines
CoV immunoprotective vs immunopathogenic
immune response
• Antibody enhancement of infection
• Feline enteric CoV (FECV) causes mild
or 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 Perlman, Nat Rev Immun 2005
• ADE of infection has not been
demonstrated in vivo with SARS-
CoV vaccinesAntibody 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)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
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
• Tested 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 oldEosinophilic 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 Tseng, PLoS ONE, 2012 response
DIV vaccination predisposes to enhanced lung
pathology
Bolles et al J of Virol 2011What 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
proteinSARS-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
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?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, 2017SARS-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
SARS-CoV-2 Vaccine Pipeline
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
https://www.cdc.gov/vaccines/parents/infographics/journey-of-child-vaccine.html
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• 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-trackerCEPI- 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
• 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-yModerna 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
Phase 1: ClinicalTrials.gov Identifier: NCT04283461 Phase 2: ClinicalTrials.gov Identifier: NCT04405076
https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-
positive-interim-phase-1-data-its-mrna-vaccineModerna 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-vaccineModerna 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
Phase 1: ClinicalTrials.gov Identifier: NCT04283461
https://investors.modernatx.com/news-releases/news-release-details/moderna-
announces-first-participants-each-age-cohort-dosed-phase
https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-
phase-1-data-its-mrna-vaccineBioNTech-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
ClinicalTrials.gov Identifier: NCT04368728 (US) ClinicalTrials.gov Identifier: NCT04380701 (Germany)
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_1339865DNA 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• 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-yCanSino 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: NCT04341389Immunogenicity of CanSino Ad5 vaccine CD8+ T cells, Day 14 CD4+ T cells, Day 14
https://covid19vaccinetrial.co.uk/about
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-trialsChAdOx1 nCoV-19 Phase 1 trial
Dose : 5x1010
viral particles
https://covid19vaccinetrial.co.uk/phase-i-trial-explained
ClinicalTrials.gov Identifier: NCT04324606AstraZeneca 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• Licensed protein subunit vaccines: • Licensed Virus like particle vaccines:
• Influenza, many others • Human papillomavirus
• Investigational coronavirus vaccines (many) • Investigational coronavirus vaccine
• Novavax Phase 1/2 start May 2020 • Medicago (phase 1 July/August 2020)
• Clover Biopharmaceuticals Inc. + GSK Adjuvant, Dynavax
• Phase 1 June 20, 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-yNovavax: 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/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=805008478https://marchforscience.org/keep-calm-and-flatten-the-curve/
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