ANNA DURBIN, MD - Center For ...
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ANNA DURBIN, MD
Professor of Medicine and Public Health Johns Hopkins Center for Immunization Research
STUART RAY, MD
Professor of Medicine Vice Chair of Medicine for Data Integrity and Analytics
NÍDIA SEQUEIRA TROVÃO, MSc, PhD
Division of International Epidemiology and Population Studies Fogarty International Center,
National Institutes of Health
Feb 22, 2021
Goals and Objectives
• By the end of today’s session, participants will be able to:
• Describe the early evolution of SARS-CoV-2
• Define viral variants and describe how they evolve
• Compare and contrast the most well-characterized variants identified to date
• Describe what is known regarding the potential impact of described variants
on the effectiveness of several currently-available or soon-to-be-available
vaccines
Clinical Case/Conundrum I
• A 45 year old man with a past medical history of antiphospholipid syndrome
presents with fever
• SARS-CoV-2 NP PCR is positive
• Treated with Remdesivir X 5 days, discharged day 5
• Past medical history
• Antiphospholipid syndrome complicated by diffuse alveolar hemorrhage
• Medications
• Glucocorticoids
• Cyclophosphamide
• Rituximab
• Eculizumab
Choi et al. 2020. NEJM.
Clinical Case/Conundrum I
• Develops abdominal pain, fatigue, dyspnea that persists for several months
• Treated with increased doses of corticosteroids
• Ct value day 39 37.8 à suggests infection resolving
Develops hypoxia, Ct value 15.6, concern for
immune suppression recurrence, given casirivimab Passes
escalated and imdevimab
Day 0 72 days post initial infection 111 days 128 days 143 days 150 days 154 days
Presents with hypoxia, Ct value 32.7, concern for Hypoxemic respiratory
PCR positive, Ct 27.6, recurrence, given 5 days failure à intubated,
treated with 10 days RDV RDV and additional RDV
immune suppression
Choi et al. 2020. NEJM.
Clinical Case/Conundrum II • You are the provider for a 37-year-old man whose elderly parents have not seen their grandchildren, ages 6 and 2 years, in the past year • The parents, who live St. Louis, have had the good fortune of completing the mRNA vaccine series (one with Moderna, one with Pfizer-BioNTech) • Your patient’s: • Father has type 2 diabetes, hypertension, and is overweight • Mother has rheumatoid arthritis managed with etanercept
Clinical Case/Conundrum II • Your patient’s parents have vigilantly followed precautions for the past year to avoid contraction of SARS-CoV-2 infection. • They are desperate to see their grandchildren, but worry about getting infected with one of the new SARS-CoV-2 variants.
Clinical Case/Conundrum II
• What information should you bring to shared decision-making with
your patient when he asks whether his parents may see their
grandchildren?
• Risk to the parents associated with travel?
• Risk that the 2-year-old (in day care) might transmit (variant) virus to the
grandparents?
• Risk that the parents might transmit (variant) virus to the children?
• Should the parents undergo testing or quarantine before seeing their
grandchildren?
• Risk mitigation with masks?
SARS-CoV-2 Evolution and Variants
Jan 30 – Feb 3 Peng Zhou, et al. Nature 2020; 579(7798):270-3 Roujian Lu, et al. Lancet 2020; 395(10224):565-74 Fan Wu, et al. Nature 2020; 579(7798):265-9 For the most current (& some interactive) analyses, see: http://virological.org/ https://nextstrain.org/groups/blab/sars-like-cov
Early evolution of SARS-CoV-2
The viral cause of COVID-19 – looking back to Jan 31, 2020
Maximum divergence at end of January
2020 was ~7 substitutions.
Serial time was about 4-5 days (from
infection of one person to infection of
the next)
Little or no immunity could
shape SARS-CoV-2 evolution
https://nextstrain.org/ncov/global?dmax=2020-01-31&l=clock&m=divWhat is a variant? How do they evolve?
Cell infection
Viral replication
Mutations
Variant: group of viruses that share the
same inherited set of distinctive mutationsSpike is critical for cell invasion by the virus and is the
primary target for human immune response
RBD
Viral membraneFitness: positive, neutral, negative evolution
Advantageous
Frequency of mutation
in the population
Advantageous
Deleterious
More Less Time
diversity diversitySeveral variants of SARS-CoV-2 have arisen
Lineag Varian
Mutation Status
e t
Appeared in early 2020 and
D614G B.1 -
spread around the world.
https://gisaid.org
https://nextstrain.orgSeveral variants of SARS-CoV-2 have arisen
Mutation Lineage Variant Status
N501Y
P681H Emerged in Britain in December and is
B.1.1.7 501Y.V1 roughly 50 percent more infectious. Now
H69-V70 and Y144/145 detected in over 70 countries and 33 states.
deletions
N501Y
Emerged in South Africa in December.
K417N B.1.351 501Y.V2
Reduces the effectiveness of some vaccines.
E484K
N501Y
Emerged in Brazil in late 2020. Has
K417T P.1 501Y.V3
mutations similar to B.1.351.
E484KConvergent evolution: 484K & 501Y repeatedly
emerging across the world
501Y.V3 (P.1) Brazil
501Y.V1 (B.1.1.7) UK
501Y.V2 (B.1.351) South Africa
https://gisaid.org
https://nextstrain.orgEvolving faster than “parents” & “siblings”
501Y.V1 (B.1.1.7) UK 501Y.V2 (B.1.351) South Africa 501Y.V3 (P.1) Brazil
https://gisaid.org
https://nextstrain.orgHypothesis: within-host evolution occurring
during prolonged infection
Persistence and Evolution
of SARS-CoV-2 in an
Phylogenetic tree with patient Immunocompromised Host
sequences (red arrow) at four time
points with high levels of SARS-
CoV-2 viral loads
484K and 501Y observed Driven by natural
during this evolution selection for immune
escape
Choi et al. 2020. NEJM.Substantial increase in spike S1 amino acid
substitutions in VOCs
Spike S1 rate of 2.9 subs
per year similar to rate in
head domain of influenza A
H3N2
Drop in neutralization titer
(Tegally et al. 202Implications for vaccine
efficacy
0. medRxiv.)
*mRNA vaccines allow faster turnarounds
and may push for more regional strategiesSepulcri C, et al. (Univ Genoa)
Prolonged infectivity (likely) [preprint] 60-70 yo M with mantle cell
lymphoma being treated with
R-BAC (R = rituximab)
4 units IVIG, one unit of CP,
4 courses of remdesivir
Duration of high-level SCV2 RNA:
8 months
= positive culture (Vero E6)
Day 268 strongly positive at Ct 22
Clade B.1.1
Accumulated 20 aa substitutions
including Spike 69 & 70 subst
https://www.medrxiv.org/content/10.1101/2021.01.23.21249554v1.full.pdfResources – up-to-date SCV2 variant info
• Pango Lineages report: https://cov-lineages.org/global_report.html
• Abundantly linked resources for each major lineage, e.g. the P.1 Brazilian
variant: https://cov-lineages.org/global_report_P.1.html
• Emma Hodcroft’s excellent CoVariants page: https://covariants.org/
• Detailed information and links for key substitutions, e.g. Spike N501Y shared
by the 3 current variants of concern https://covariants.org/variants/S.N501Variants and Efficacy of SARS-CoV-2 Vaccines
Pfizer vaccine and UK & SA variant
• Made recombinant viruses by
introducing specific mutations
into the USA-WA1/2020
background
• Mutant Δ69/70+N501Y+D614G
represents UK variant
• Mutant E484K+N501Y+D614G
represents B.1.351 SA variant
Xie Nat Med 2021
but does not include all of its
mutationsPfizer vaccine and SA variant
Δ242- B.1.351- B.1.351-
WT 244+D614G RBD+D614G Spike
Geometric Mean PRNT50
502 485 331 184
• Neutralizing antibody titers induced by Pfizer
vaccine against recombinant strains containing
mutations from the SA variants. B1.351-spike
contains all mutations found in the SA spike
variant
• Although titers reduced, they are reduced
GMT > 100
Liu et al NEJM 2021
February 23, 2021 24Moderna vaccine
• Used VSV pseudovirus
neutralization assay
• Neutralization of B.1.1.7
variant not affected
• Neutralization of B.1.351
(SA variant) reduced
• GMTiter > 100
Wu, et al NEJM 2021
February 23, 2021 25Efficacy of Johnson & Johnson
• Single dose
• Efficacy against moderate to severe COVID
• 72% effective in the US
• 66% in Latin America
• 57% in South Africa (95% of cases due to B.1.351 variant)
• 85% effective in preventing severe disease and 100% effective
against hospitalization and death (even SA variant)
February 23, 2021 26Efficacy of Novavax
• Recombinant SARS-CoV-2 nanoparticle constructed from the full-
length spike protein (pre-fusion stabilized)
• Entered clinical trials in US in December, has been in clinical trial in
UK and South Africa
• Phase 3 results from UK & South Africa released Jan. 28
• 89.9% efficacy in UK with > 50% of cases from variant UK strain (62
cases)
• 60% efficacy in S. Africa against mild, moderate, or severe COVID (based
on 44 cases, 92% were S. Africa variant)
• Only 1 case was severe (placebo group)
February 23, 2021 27Variants & Vaccines Summary • Neutralizing antibodies induced by all current COVID vaccines are less potent against the SA variant and highly potent against UK variant • However, the antibodies are still able to neutralize the SA variant • The vaccine currently in efficacy trials in SA (J&J) has shown excellent efficacy against severe and hospitalized COVID despite lower efficacy against symptomatic COVID • It is expected that the vaccines will have lower efficacy against symptomatic COVID caused by the SA variant however they will offer significant protection against severe and hospitalized disease • Will need more data to confirm this
Q &A Please enter your questions into the chat!
SLIDES & RECORDINGS ARCHIVED ONLINE https://bit.ly/2Y2DIDj
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