SARS-CoV-2

MUTATIONS AND VARIANTS

ZEN AHMAD
KSM/BAGIAN ILMU PENYAKIT DALAM DIVISI PULMONOLOGI
RUMAH SAKIT UMUM PUSAT Dr. MOHAMMAD HOESIN PALEMBANG
FAKULTAS KEDOKTERAN UNIVERSITAS SRIWIJAYA
2021
Kasus Covid-19 (27 Mei 2021, 05.45 WIB)
DUNIA1 INDONESIA2 SUMSEL
Konfirmasi 169.049.370 1.791.221 23.594
Kematian 3.511.203 49.771 ( 2,8%) 1.199 ( 5,08%)
Sembuh 150.685.301 1.645.263 (91,9%) 21.097 (89,42%)
Kasus aktif 14.852.866 96.187 ( 5,4%) 1.298 ( 5,50%)
14.757.972 (99,4%) ringan
94.894 ( 0,6%) kritis
Kasus 154.196.504
selesai 150.685.301 (98%) Sembuh
3.511.203 (2%) Meninggal 49.771 Meninggal 1.199 meninggal
Sumber : 1. https://www.worldometers.info/coronavirus/ 2. https://infeksiemerging.kemkes.go.id/dashboard/covid-19
Grading gejala Covid-19
Normal/Ringan

Sedang

Berat

Kritis

Source : https://www.visualcapitalist.com
Pharmaco-therapy confirmed Covid-19
Ringan
Tanpa Gejala Sedang (moderate) Berat/Kritis
(uncomplicated)

▪ Obat komorbid ▪ Obat komorbid dan komplikasi

▪ Vit. C drip 200-400mg/8 jam ▪ Vit. C drip 200-400 mg/8 jam
▪ Vit. C ▪ Vit. C oral
▪ Vit. D ▪ Vit B1 1 amp/24 jam
• Oral , 3-4 x 500 mg (14 ▪ Vit D ▪ Vit. D
hari) ▪ Azitromisin 500 mg oral/IV, atau
▪ Azitromisin 1x500mg (5 hr) ▪ Azitromisin 500 atau levofloxacin
• Tablet isap 2 x 500mg levofloxacin 750 mg/24 jam
(Oral/IV) 5- 7 hri
(30 hari) ▪ Antivirus oral/IV (5-7 hari)
▪ AB pada sepsis bakterial
• Multivitamin (C,B, E, • Oseltamivir 2 x 75mg
▪ Antivirus ▪ Antivirus
Zink)1-2 tablet/24 jam 5-7 hr)
• Favipiravir 2x1600mg,oral • Favipiravir 2x1600mg,oral hari
(30 hr) • Favipiravir 2 x 1600 mg (Hari
hari 1, 2x600 mg (hari 2-5) 1, 2x600 mg (hari 2-5)
1), 2x600mg (hr 2-5)
▪ Vitamin D • Remdesivir 200 mg IV drip/3 • Remdesivir 200 mg IV drip/3
(5 hari).
• Suplemen 400-1000 IU/ jam (Hr 1) lanjut 100 mg/3 jam jam (Hr 1) lanjut 100 mg/3 jam
▪ Parasetamol bila demam (Hr 2-5) (Hr 2-5)
hari
▪ OMAI *sesuai kondisi pasien ▪ Antikoagulan# ▪ Antikoagulan
• Obat 1000-5000 IU/hari ▪ Corticosteroid
▪ Simptomatis: PCT, dll.
▪ Obat komorbid dan komplikasi
▪ Obat komorbid dan komplikasi ▪ Tatalaksana shock
▪ Obat suportif (IVIG, MSCs, Anti
IL-6 dsb)
PAPDI, PDPI, PERKI, PERDATIN, IDAI.
Pedoman Tatalaksana COVID-19. Edisi 3; Desember 2020
Corona
Coronavirus
virus
Science has responded quicker to Covid-19 than it did to SARS
WHO first informed of outbreak
23 30 36 Pathogen identiifed
Virus sequenced
Covid Testing begins
19

33

86 126 151 231

Outbreak
SARS 149 declared
contained

Days since first case

Structure of Coronavirus
Schematic structure /Structural proteins

Similarity percentages of Coronavirus

C. ORFs of SARS-CoV, MERS-CoV, and SARS-CoV-2

Rezaei Z. Molecular Insights into COVID-19 Pathophysiology, Immune Pathogenesis, Detection, and Treatment
DNA AND CELL BIOLOGY Volume 40, Number 7, 2021
Diagram of the CORONAVIRUS GENOME

• Coronavirus mengandung
30.000 bp RNA

• Informasi genetik ini membu-

at virus dapat menginfeksi sel
manusia dan berkembang biak

auuaaagguuuauaccuucccagguaacaaaccaaccaacuuucgaucucuuguagaucuguucucu
aaacgaacuuuaaaaucuguguggcugucacucggcugcaugcuuagugcacucacgcaguauaauu
aauaacuaauuacugucguugacaggacacgaguaacucgucuaucuucugcaggcugcuuacgguu
ucguccguguugcagccgaucaucagcacaucuagguuucguccgggugugaccgaaagguaag
Struktur SARS CoV-2
Web genomic surveilance
PANGO lineages
https://cov-lineages.org

GISAID
Global Initiative on Sharing All Infuenza Data
https://www.gisaid.org/hcov19-variants/

SPHERES
SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology, and Surveillance
https://www.cdc.gov/coronavirus/2019-ncov/covid-data/spheres.html
NEXTSTRAIN
https://nextstrain.org/sars-cov-2

MICROREACT
https://microreact.org/showcase
Istilah
Istilah Makna
Mutasi Kesalahan pada pembuatan copy coronavirus yang baru

Lineage Percabangan silsilah keluarga (garis keturunan) virus

Variant Kelompok coronavirus dengan mutasi yang sama
• Variants of interest (diturunkan)
• Variants of concern
• Varians o high consequence
Strain Mutasi yang terakumulasi dalam satu garis keturunan
Terdapat perbedaan jelas cara dan fungsi virus
Lineage
Pertanyaan tentang variant baru

• Apakah penularannya lebih cepat

• Apakah klinis lebih ringan atau lebih berat
https://www.cdc.gov/coronavirus/2019-ncov

• Apakah masih bisa didiagnosis oleh pemeriksaan viral saat ini

• Apakah ada perbedaan respon pengobatan
• Apakah mempengaruhi efektivitas vaksin COVID-19
SARS-CoV-2 Variants
Variant of Interest
A variant with specific genetic markers
that have been associated with :
• Changes of receptor binding
• Reduced neutralization by
antibodies generated against
previous infection or vaccination
• Reduced efficacy of treatments
• Potential diagnostic impact
• Predicted increase in
transmissibility or disease severity.
Evidence that it is the cause of an
increased proportion of cases or unique
outbreak clusters
Limited prevalence or expansion
Sumber: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
Variant of Concern
A variant for which there is evidence :
• An increase in transmissibility
• More severe disease
(Hospitalizations/deaths )
• Significant reduction in
neutralization by ABs (previous
infection /vaccination)
• Reduced effectiveness of
treatments or vaccines,
• Diagnostic detection failures
Possible attributes of a variant of interest
Evidence of impact on diagnostics,
treatments, or vaccines
Evidence of increased transmissibility
Evidence of increased disease severity
Variant of high consequence
A variant who has clear evidence:
• Prevention measures or medical
countermeasures have significant
reduce effectiveness relative to
previously circulating varians
Possible attributes of a variant of concer
Impact on Medical Countermeasures
• Demonstrated failure of diagnostics
• Evidence to suggest a significantly
reduction in vaccine effectiveness
• Significantly reduced susceptibility
multiple EUA or approved
therapeutics
• More severe clinical disease and
increased hospitalizations
SARS-CoV-2 Variants of Interest
Lineage
Spike protein subsitutions
B. 1.525 A67V, 69del, 70del, 144del,
E484K, D614G, Q677H, F888L
B.1.526 L5F, T95I, D253G, S477N,
E484K, D614G, A701V
B.1.526.1 D80G, 144del, F157S, L452R,
D614G, T791I, T859N, D950H
B.1.617 L452R, E484Q, D614G
B.1.617.1 T95I, G142D, E154K, L452R,
E484Q, D614G, P681R, Q1071H
B.1.617.2 T19R, (G142D), 156del, 157del,
R158G, L452R, T478K, D614G,
P681R, D950N
B.1.617.3 Spike: T19R, G142D, L452R,
E484Q, D614G, P681R, D950N
P2 E484K, F565L, D614G, V1176F
https://www.cdc.gov/coronavirus
Name First Detected Attributes
20A/S:484K United Kingdom/Nigeria
Desember 2020 Potential reduction in neutralization by some
20C/S:484K United States (New York) EUA monoclonal antibody treatments
October 2020 Potential reduction in neutralization by
20C United States (New York) convalescent and post-vaccination sera
October 2020
20A India – February 2021 Potential reduction ............; Slightly reduced
neutralization by post-vaccination sera
20A/S:154K India – December 2020 Potential reduction in neutralization by some
7, 14
EUA monoclonal antibody treatments
20A/S:478K India – December 2020
Potential reduction in neutralization by post-
vaccination sera
20A India – October 2020
20J Brazil – April 2020 Potential reduction ..........,; Reduced
neutralization by post-vaccination sera
 SARS-CoV-2 Variants of concern
Line- Spike protein Name First Attributes
age subsitutions Detected
B.1.1.7 69del, 70del, 144del, E484K, 20I/501Y.V United • 50% increased transmission
5

S494P, N501Y, A570D, 202012/011 Kingdom • Potential increased severity based on hospitalizations and CFR
6

D614G, P681H, T716I, • No impact on susceptibility to EUA monoclonal AB treatments

7,14

S982A, D1118H, K1191N • Minimal impact on neutralization by convalescent/post-vaccination

16
B.1.351 D80A, D215G, 241del, 20H/501.V2 South Africa • 50% increased transmission
242del, 243del, K417N, • Significant decrease in susceptibility to the combination of
7
E484K, N501Y, D614G, bamlanivimab and etesevimab monoclonal AB treatment, but other
14
A701V EUA monoclonal antibody treatments are available
• Reduced neutralization by convalescent and post-vaccination sera
B.1.427 L452R, D614G 20C/S:452R US(California) 21
• 20% increased transmissibility
B.1.429 S13I, W152C, L452R, D614G 20C/S:452R US(California) • Modest decrease in susceptibility to the combination of bamlanivi-
mab/etesevimab; however, the clinical implications of this decrease
7
are not known. Alternative monoclonal AB treatments are available
• Reduced neutralization by convalescent and post-vaccination sera
P.1 L18F, T20N, P26S, D138Y, 20J/501Y.V3 Japan/ • Significant decrease to the combination of bamlanivimab and
7
R190S, K417T, E484K, N501Y, Brazil etesevimab monoclonal AB treatment, but other EUA monoclonal
14
D614G, H655Y, T1027I AB are available
• Reduced neutralization by convalescent and post-vaccination sera
B.1.1.7 Lineage
• 30 -50% lebih infeksius
• 55% lebih mematikan
• Vaksin masih bekerja baik
• Mutasi sering pada spike
N501Y; virus nempel lebih erat
dg sel manusia
P681H; kerja protein spike lebih
efisien
Delesi H69V70 dan Y144/145;
perubahan bentuk spike dan
menghindari beberapa AB
Sebaran B1.1.7 (25-05-21)
Statistic Information
Countries with 137
sequences
Sequence count 701235
Countries 1. United Kingdom 43. Cambodia 178
240396 44. Singapore 170
2. United States of 59. Thailand 74
America 134051 87. Indonesia 16
3. Germany 75592 98. Malaysia 8
32. Philippines 629 137. Vietnam 1
First detected United Kingdom
Earliest sample 2020-09-20
date
Defining SNPs aa:orf1ab:T1001I aa:S:T716I
aa:orf1ab:A1708D aa:S:S982A
aa:orf1ab:I2230T aa:S:D1118H
del:11288:9 aa:Orf8:Q27*
del:21765:6 aa:Orf8:R52I
del:21991:3 aa:Orf8:Y73C
aa:S:N501Y aa:N:D3L PANGO lineages
aa:S:A570D aa:N:S235F https://cov-lineages.org/global_report_B.1.1.7.html
aa:S:P681H
B.1.351 Lineage
• Varian 20H/501Y.V2
• Identifikasi pertama di Afsel
• Efektivitas vaksin turun??
Sembuh dari varian lain tetap
kena B.1.351 sebab AB tak dapat
menangkap erat virus
• Mutasi pada spike
N501Y; Virus nempelnya erat dg sel
K417N; Virus nempelnya erat dg sel
E484K, virus mampu menghindar
dari beberapa AB
Sebaran B1.351(25-05-2021)
Statistic Information
Countries with 92
sequences
Sequence count 18519

Countries 1. South Africa 31. Malaysia 66

2863 58. Thailand 8
2. France 1880 77. Indonesia 2
3. Germany 1800 85. Brunei 1
8. Philippines 684 92. French Guiana 1
22. Singapore 173

First detected South Africa

Earliest sample 2020-09-01

Defining SNPs aa:E:P71L

aa:S:K417N
aa:N:T205I
aa:S:A701V
aa:orf1a:K1655N
aa:S:N501Y
aa:S:D80A PANGO lineages
aa:S:E484K
aa:S:D215G https://cov-lineages.org/global_report_B.1.1.7.html
P.1 Lineage
• Varian 20J/501Y.V3
• Identifikasi pertama di Jepang
• Mampu mengatasi kekebalan yang
ditimbulkan oleh varian lain
• Mutasi pada spike
N501Y; Virus nempelnya erat dg sel
K417T; Virus nempelnya erat dg sel
E484K, virus mampu menghindar dari
beberapa AB
Sebaran P.1 (25-05-2021)
Statistic Information
Countries with 51
sequences
Sequence count 20093
Countries 1. USA 10422 33. Singapore 5
2. Brazil 4772 42. Philippines 2
3. Italy 867 51. Thailand 1

First detected Brazil

Earliest sample 2020-11-03
date
Defining SNPs aa:orf1ab:S1188L aa:S:K417T
aa:orf1ab:K1795Q aa:S:E484K
del:11288:9 aa:S:N501Y
aa:S:L18F aa:S:H655Y
aa:S:T20N aa:S:T1027I
aa:S:P26S aa:orf3a:G174C
aa:S:D138Y aa:orf8:E92K
aa:S:R190S aa:N:P80R PANGO lineages
https://cov-lineages.org/global_report_B.1.1.7.html
B.1.617 Lineage
• Terjadi mutasi pada dua titik
E484Q dan L452R, sehingga disebut
“double mutant”
• E484Q lokasinya sama dg E484K,
Mutasi “Eek” mengakibatkan virus
mampu menghindar dari beberapa
AB
• Mutasi N501Y mengakibatkan virus
nempel lebih erat dg sel
• Mutasi K417T mengakibatkan virus
nempel lebih erat dg sel
Sebaran B.1.617.2 (19-05-2021)
Statistic Information
Countries with 50
sequences
Sequence count 9320
Countries 1. UK 6050 19. Indonesia 24
2. India 1205 37. Malaysia 3
3. USA 896 38. Cambodia 1
6. Singapore 100, 50. Morocco 1

First detected India

Earliest sample 2020-12-10
date
Defining SNPs S:T19R M:I82T
S:L452R ORF7a:V82A
S:T478K ORF7a:T120I
S:P681R N:D63G
S:D950N N:R203M
ORF3a:S26L N:D377Y PANGO lineages
https://cov-lineages.org/global_report_B.1.1.7.html
Sekuens SARS CoV-2 di Indonesia (22 Mei 2021)
https://www.gisaid.org/phylodynamics/indonesia/
Temuan varian B.1.617 (8 mei 2021)
Jejaring Surveilans Genom Indonesia
Institusi Cakupan
BALITBANGKES Sumbar, Sumsel, Lampung, FK UNPAD Jawa Barat
Riau, Babel, Kalteng, Kalsel,
Kaltim, Kalut, Sulawesi, Bali,
Maluku, Maluku Utara, NTB
BALAI Penelitian dan Aceh SITH ITB Jawa Barat
Pengembangan Kesehatan Aceh
BALAI Penelitian dan Papua, Papua Barat FK UGM DIY, Jawa Tengah
Pengembangan Kes. Papua
BBTKL Surabaya Jawa Timur FK UNS Jawa Tengah
BB Penelitian & Pengembangan Jawa Tengah FK UI DKI Jakarta
Vektor & Reservoir Penyakit
LBM Eikjman DKI, NTT, Bali, Sulut UIN S. Hidayatullah Banten
BPPT Jawa Barat, Banten UPH (MRINUPH)
LIPI Banten, Bogor, Depok ITD UNAIR Jatim; Sumut
UNAND FK Univ Tanjungpura Kalimantan Barat
Simpulan
• Kasus Covid-19 masih terus meningkat
• Variant SARS-CoV-2 mulai danterus bermunculan
• Variant ini dihubungkan dengan
▪ Penularan yang lebih cepat
▪ Klinis lebih berat
▪ Kesulitan diagnosis
▪ Respon pengobatan yang turun
▪ Penurunan efektivitas vaksin COVID-19

• Sumsel termasuk daerah di Indonesia dengan

rekuensi variant baru yang cukup banyak
TERIMA KASIH