NIC Data to Global Vaccine Decisions

Disclaimer

The findings and conclusions in this presentation are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.

References to non-CDC sites on the Internet do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites.

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Training Objectives

Trainees should be able to

Productionalize their influenza genomic data processing
Submit timely, high-quality data to GISAID and NCBI
Perform informatic analyses (e.g., phylogenetic trees, amino acid mutations) of influenza sequences
Generate genomic surveillance reports on circulating subtypes and clades

Training scene illustration

What is Influenza?

RNA virus in the family Orthomyxoviridae
Four types: A, B, C, D — Type A is the most clinically significant
Causes seasonal epidemics and occasional pandemics
Infects the respiratory tract; spreads via droplets and aerosols

Note

Type A infects humans, birds, pigs, and more — giving it broad pandemic potential.

The Annual Global Burden of Influenza

Morbidity & Mortality

Metric	Estimate
Total infections	~1 billion/year
Severe illness cases	3–5 million/year
Respiratory deaths	290,000–650,000/year
US hospitalizations	120,000–710,000/year
US deaths	6,300–52,000/year

WHO (2024); CDC (2025)

Economic Impact (US)

Cost Category	Estimate
Direct medical costs	~$3.2–3.7 billion/year
Lost productivity	~$8.0–16.3 billion/year
Total societal burden	up to ~$87 billion/year
2023–24 season alone	~$29 billion

Molinari et al. (2007); Putri et al. (2018); GHLF/AVAC (2024)

Warning

High-risk groups: Adults ≥65 account for the majority of deaths — mortality rates are 26× higher in this group than in those under 65. Burden is also disproportionately high in low- and middle-income countries, where 99% of severe influenza in children under 5 occurs.

Virion Structure

The influenza virion has three main layers:

Layer	Components
Envelope	Lipid bilayer (host-derived); HA, NA, M2 surface proteins
Matrix	M1 protein shell beneath the envelope
Core	8 RNA segments + nucleoprotein (NP) + polymerase (PB1, PB2, PA)

HA — binds host cell receptors
NA — releases new virions from the host cell
PB1/PB2/PA — replicate and transcribe the viral genome

Influenza virion structure diagram

Source: ViralZone — Influenza A, Swiss Institute of Bioinformatics

The Genome

Influenza A carries 8 segments of negative-sense, single-stranded RNA, each encoding key proteins:

Segment	Key Protein	Role
4	HA	Attachment & membrane fusion
6	NA	Virion release (sialidase)
1–3	PB2, PB1, PA	RNA polymerase complex
5	NP	Encapsidates RNA
7–8	M1/M2, NS1/NEP	Matrix, ion channel, immune evasion

Subtypes are named by HA & NA combination — e.g., H1N1, H3N2, H5N1

Influenza A genome segment diagram

Source: ViralZone — Influenza A, Swiss Institute of Bioinformatics

¿Why?

Influenza mutates rapidly (drifts) and evades previous host immunity

Antigenic drift figure

Vaccine antigen must be updated most years

Genetic Change: Drift vs. Shift

Antigenic Drift 🚣

Gradual point mutations in HA/NA
Error-prone polymerase (no proofreading)
Slow immune evasion over time
Reason flu vaccines are updated annually

Antigenic Shift 💥 🔀

Sudden swap of whole gene segments (reassortment)
Happens when two strains infect the same cell
Can trigger pandemics (e.g., 2009 H1N1)

Vaccine strain is chosen ~8 months before flu season

WHO convenes technical consultations to recommend viruses for three components:
- A(H1N1)pdm09, A(H3N2) and B/Victoria lineage
Two recommendation tracks:
- Egg-based vaccines
- Cell / recombinant / nucleic acid–based vaccines
Prototype names may differ by platform — both represent the best candidate for subtype

Timing of Influenza Vaccine Recommendations

6–8 months for the production, regulatory approval and distribution of the manufactured vaccines

Vaccine strain selection timing diagram

Influenza Vaccine Composition Meeting Decision Process

Goal — Identify antigens that elicit immunity against diverse / diverging future viruses

Review influenza activity, trends, geography

Epidemiologic and clinical data

Where are recent epidemics occurring
Virus surveillance

Global Influenza Surveillance and Response System (GISRS) labs test 50–150 thousand samples per week year-round: identify influenza positive specimens; type and influenza A subtype

Review laboratory data of recently collected viruses

Genomic Characterization

Genetic subclades that have emerged; geographic spread and proportion; forecasting predominance

Antigenic Characterization

Level of antigenic drift from progenitors and/or vaccine references

Data Sharing and Integration across GISRS

Genetic and Antigenic data integration
Phylogenetics
Phylogeography
Fitness forecasting
Antigenic cartography
Antiviral susceptibility
Human Serum Panels
Candidate Vaccine Virus (CVV) Reagent sharing

Human serology data and vaccine effectiveness

Post-vaccination and post-exposure studies

Comparative analysis of co-circulating antigenic variants to identify those that pose the greatest risk of immune escape

Global Influenza Vaccine Effectiveness (GIVE) Collaboration: VE studies — previous and current season interim results

Review Candidate Vaccine Virus availability

New CVVs

Analysis of the availability and characterization status of candidate vaccine viruses for each platform
Review of cell or egg-adaptation mutations in CVVs
Review of high-growth reassortants

VCM FAQ — WHO · Russell, C.A. et al., Vaccine (2008) doi.org/10.1016/j.vaccine.2008.07.078

Slide credit and thanks to Dr. Becky Kondor

It all begins with YOU!

Global Influenza Surveillance and Response System (GISRS)

Influenza Vaccine Composition Meeting Decision Process

Goal — Identify antigens that elicit immunity against diverse / diverging future viruses

Review influenza activity, trends, geography

Epidemiologic and clinical data

Where are recent epidemics occurring
Virus surveillance — GISRS labs test 50–150 thousand samples per week year-round: identify positives; type and subtype

Review laboratory data

Data Sharing & Integration across GISRS

Human serology and vaccine effectiveness

Review CVV availability

Slide credit and thanks to Dr. Becky Kondor

Global Circulation of Seasonal Influenza Viruses Since January 2024

Global circulation of seasonal influenza viruses since Jan 2024

Data reported to FluNet by GISRS National Influenza Centers in 135 member states · VCM Information meeting

Influenza activity and global distribution of type/subtype

September 1, 2025 — January 31, 2026

Influenza activity & subtype global distribution map

VCM Information meeting

Your data is leading to more refined definitions of “influenza season”

A — northern hemisphere pattern; peak influenza activity between October–April
B — northern hemisphere pattern; peak influenza activity between September–March
C — tropics; influenza activity between September–March
D — southern hemisphere pattern; influenza activity between May–November; additional activity in other months
E — southern hemisphere pattern; peak influenza activity between May–November

medRxiv link

Influenza Vaccine Composition Meeting Decision Process

Goal — Identify antigens that elicit immunity against diverse / diverging future viruses

Review influenza activity, trends, geography

Review laboratory data of recently collected viruses

Genomic Characterization — genetic subclades that have emerged; geographic spread and proportion; forecasting predominance

Antigenic Characterization — level of antigenic drift from progenitors and/or vaccine references

Data Sharing & Integration across GISRS

Human serology and vaccine effectiveness

Review CVV availability

Slide credit and thanks to Dr. Becky Kondor

Genomic Surveillance: Nomenclature for Hemagglutinin (HA) and Neuraminidase (NA)

HA and NA nomenclature phylogenetic tree

Goal: Tracking of relative frequencies of co-circulating subclades

Criteria for Subclade Definition:

Size and dynamics of the subclade — larger, recently expanded groups prioritized
Divergence — more genetic changes since the parent group given higher priority
Specific amino acid substitutions — significant substitutions that may affect phenotype

New subclade and aliases about four times a year — usually after VCM

Influenza Resp Viruses 20(2), 13 Feb 2026 · DOI 10.1111/irv.70230 · clades.nextstrain.org · Slide credit: Dr. Becky Kondor

A(H3N2) Viruses in the 25/26 Northern Hemisphere

Number of A(H3N2) viruses detected by GISRS

VCM Information meeting

Influenza A(H3N2) virus activity

A(H3N2) virus activity global map and chart

Data source: FluNet, Global Influenza Surveillance and Response System (13 February 2026) · VCM Information meeting

A(H3N2) HA phylogeography

A(H3N2) HA phylogeography tree colored by region

Region

North America
South America
Europe
Africa
Middle East
Russia
E / SE Asia
Oceania

Figure source: University of Cambridge · clades.nextstrain.org · VCM Information Meeting · Slide credit: Dr. Becky Kondor

Global A(H3N2) HA clade diversity: Sep 2025 to Jan 2026

Global A(H3N2) HA clade diversity by region donut charts

Data source: clades.nextstrain.org · Slide credit: Dr. Becky Kondor

A(H3N2) Extended Diversity Plot — Global view

Feb 2025 – Jan 2026

Data source: · clades.nextstrain.org · Slide credit: Dr. Becky Kondor

The graphic on the left shows an extended diversity plot of the influenza A(H3N2) clades and subclades globally from February 1, 2025 to present. The vast majority of viruses belonged to clade 2a.3a.1 and viruses belonging to the J.2 subclades predominated globally. At the start of this reporting period, viruses belonging to subclade J.2 predominated although viruses belonging to subclade J.2.2, J.2.3, J.2.4, and J.2.5 co-circulated. Since June 2025, detections of viruses belonging to the K subclade increased, and viruses belonging to subclade K have predominated in recent months. Viruses belonging to subclades J.2, J.2.3, and J.2.4 continue to co-circulate but at much lower levels.

The graphic on the right shows an extended diversity plot of the influenza A(H3N2) clades and subclades in the United States from September 20, 2025 to present. All viruses belonged to clade 2a.3a.1, and viruses belonging to subclade K predominated throughout the reporting period. Viruses belonging to subclades J.2.3 and J.2.4 continue to co-circulate but at much lower levels.

A(H3N2) Extended Diversity Plot by Geographic Region

February 2025 – February 2026

HA Clade_Subclade

2a.3a_G.1.3.1
2a.3a1_J
2a.3a1_J.1
2a.3a1_J.1.1
2a.3a1_J.2
2a.3a1_J.2.1
2a.3a1_J.2.2
2a.3a1_J.2.3
2a.3a1_J.2.4
2a.3a1_J.2.5
2a.3a1_J.4
2a.3a1_K

A(H3N2) extended diversity plot stacked by geographic region

Data source: · clades.nextstrain.org · Slide credit: Dr. Becky Kondor

Influenza phenotyping relies heavily on ferrets and hemagglutinin inhibition assays

HI antigenic analysis of A(H3N2) viruses

	Cell Cro/10136RV	Cell Neth/10685	Cell Syd/1359	Egg Sing/GP20238	Cell Dar/1415	Egg Dar/1454
HA subclade	J.2	J.2.3	J.2.4	J.2.4	K	K
*Reference virus*
A/Croatia/10136RV/2023 (J.2)	320	<40	40	40	<40	<40
A/Netherlands/10685/2024 (J.2.3)	80	640	<40	<40	<40	<40
A/Sydney/1359/2024 (J.2.4)	160	40	320	2560	640	640
A/Singapore/GP20238/2024 (J.2.4)	160	160	640	2560	320	320
A/Darwin/1415/2025 (K)	40	40	160	640	640	640
A/Darwin/1454/2025 (K)	<40	80	320	1280	1280	640
*Test virus*
A/Darwin/2100/2025 (J.2.2)	320	<40	40	40	<40	<40
A/Singapore/GP14404/2025 (J.2.2)	320	<40	40	40	<40	<40
A/Victoria/2797/2025 (J.2.4)	<40	<40	320	640	640	640
A/Sri Lanka/69/2025 (J.2.4)	80	40	320	2560	640	640
A/Tasmania/1035/2025 (K)	<40	<40	80	320	320	320
A/Canberra/980/2025 (K)	<40	<40	80	640	640	320
A/Sri Lanka/111/2025 (K)	40	<40	160	640	1280	1280
A/Cambodia/IKCM250152/2025 (K)	<40	<40	160	640	640	320
A/New Caledonia/195/2025 (K)	<40	<40	80	640	640	640
A/Nepal/S3684/2025 (K)	<40	<40	80	320	640	640

Source: WHO CC, Australia · VCM Information meeting · Slide credit and thanks to Dr. Becky Kondor

A(H3N2) antigenic cartography

A(H3N2) — CDC Atlanta (HINT)
A/Darwin/1415/2025-cell-like serum circle (within 8-fold of homologous titer)

A(H3N2) antigenic cartography - CDC Atlanta HINT

A(H3N2) — CC Tokyo (HI)
A/Darwin/1454/2025-egg-like serum circle (within 8-fold of homologous titer)

A(H3N2) antigenic cartography - CC Tokyo HI

Source: University of Cambridge · VCM Information meeting · Slide credit and thanks to Dr. Becky Kondor

The images shown are of antigenic relationships of A(H3N2) viruses tested in virus neutralization and hemagglutination inhibition assays at CDC and the WHO Collaborating Center in Tokyo. The antigenic cartography maps show that recently circulating J.2 viruses with additional amino acid changes in the HA (belonging to subclades J.2.3, J.2.4, J.2.5, and K) are clustering farther apart from the 2025-2026 northern hemisphere vaccine reference viruses indicating antigenic drift. The image on the left represents viruses tested in virus neutralization assays at CDC. The image on the right represents viruses tested in hemagglutination inhibition assays at the WHO Collaborating Center in Tokyo. The image on the left shows that the serum circle for post-infection ferret antisera raised against cell-propagated A/Darwin/1415/2025 recognized other K viruses well (within 8-fold homologous titers). The image on the right shows that the serum circle for post-infection ferret antisera raised against egg-propagated A/Darwin/1454/2025 recognized other K viruses well and shows cross reactivity with recent viruses belonging to some HA subclades, including J.2.4 and J.2 with the T135K amino acid change (withing 8-fold homologous titers).

Antigenic analysis of A(H3N2) viruses in HI and NT assays

Antisera to northern hemisphere 2025–2026 vaccine virus antigens

A/District of Columbia/27/2023-like Cell
2a.3a.1 (J.2) by HI

WHO CC	Like	Low (≥ 8 fold)
CDC	19 (9%)	202 (91%)
CNIC	946 (43%)	1231 (57%)
FCI	46 (18%)	216 (82%)
NIID	33 (11%)	260 (89%)
VIDRL	124 (9%)	1329 (91%)
Total	1168 (27%)	3238 (73%)

A/District of Columbia/27/2023-like Cell
2a.3a.1 (J.2) by NT

WHO CC	Like	Low
CDC	14 (12%)	104 (88%)
FCI	23 (26%)	64 (74%)
Total	37 (18%)	168 (82%)

A/Croatia/10136RV/2023-like Egg
2a.3a.1 (J.2) by HI

WHO CC	Like	Low (≥ 8 fold)
CDC	8 (4%)	213 (96%)
CNIC	520 (24%)	1657 (76%)
FCI	20 (8%)	242 (92%)
NIID	8 (3%)	285 (97%)
VIDRL	47 (3%)	1406 (97%)
Total	603 (14%)	3803 (86%)

A/Croatia/10136RV/2023-like Egg
2a.3a.1 (J.2) by NT

WHO CC	Like	Low
FCI	15 (25%)	46 (75%)
Total	15 (25%)	46 (75%)

“Low” represented titers ≥ 8-fold lower than vaccine strain homologous titer · VCM Information meeting · Slide credit: Dr. Becky Kondor

Antigenic analysis of A(H3N2) viruses in HI and VN assays

Antisera to southern hemisphere 2026 vaccine virus antigens

A/Sydney/1359/2024-like Cell
2a.3a.1 (J.2.4) by HI

WHO CC	Like	Low (≥ 8 fold)
CDC	167 (76%)	54 (24%)
CNIC	405 (72%)	154 (28%)
FCI	102 (39%)	160 (61%)
NIID	207 (92%)	18 (8%)
VIDRL	1274 (88%)	179 (12%)
Total	2155 (79%)	565 (21%)

A/Sydney/1359/2024-like Cell
2a.3a.1 (J.2.4) by VN

WHO CC	Like	Low
CDC	96 (81%)	22 (19%)
FCI	73 (84%)	14 (16%)
Total	169 (82%)	36 (18%)

A/Singapore/GP20238/2024-like Egg
2a.3a.1 (J.2.4) by HI

WHO CC	Like	Low (≥ 8 fold)
CDC	110 (85%)	19 (15%)
CNIC	368 (22%)	1279 (78%)
FCI	115 (44%)	147 (56%)
NIID	198 (88%)	27 (12%)
VIDRL	1184 (81%)	269 (19%)
Total	1975 (53%)	1741 (47%)

A/Singapore/GP20238/2024-like Egg
2a.3a.1 (J.2.4) by VN

WHO CC	Like	Low
FCI	11 (13%)	76 (87%)
Total	11 (13%)	76 (87%)

“Low” represented titers ≥ 8-fold lower than vaccine strain homologous titer · VCM Information meeting · Slide credit: Dr. Becky Kondor

Human post-vaccination serum analysis of A(H3N2) viruses (CDC data)

Human post-vaccination serum analysis CDC data

Slide credit and thanks to Dr. Becky Kondor

A(H3N2) Integrated Genotype and Phenotype Analysis

Integrated genotype-phenotype phylogenetic tree

Data source: · clades.nextstrain.org · Slide credit: Dr. Becky Kondor

A(H3N2) Circulating Subclades

Multiple subclades with additional HA substitutions co-circulating
Ferret antisera to A/District of Columbia/27/2023 (J.2) show reduced to poor reactivity with viruses from HA subclades J.2.3, J.2.4 and K
Ferret antisera to A/Sydney/3549/2024-like (J.2.4) show reduced to poor reactivity with viruses from HA subclade J.2.3 but recognised most J.2.4 viruses and many K viruses well

A/District of Columbia/27/2023

2025 SH and 2025-26 NH Vaccine

J.2

J.2.3

Emerged Fall 2024

A/Sydney/3549/2024

2026 SH Vaccine

J.2.4

Emerged Summer 2024

A/Darwin/1415/2025

2026-27 NH Vaccine

K

Emerged Summer 2025

Slide credit: Dr. Becky Kondor

Influenza A(H3N2): antiviral susceptibility

Neuraminidase inhibitors

Of 4,458 influenza A(H3N2) viruses examined by genetic and/or phenotypic analyses, two viruses showed evidence of reduced susceptibility to NAIs; both had an NA E119V substitution.

Endonuclease inhibitors

Of 4,828 A(H3N2) viruses examined by genetic and/or phenotypic analyses, nine viruses showed evidence of reduced susceptibility to baloxavir marboxil:

3 had a PA I38T substitution
3 had a PA I38I/T substitution
2 had a PA I38I/M substitution
1 had a PA E199E/G substitution

VCM Information meeting · Slide credit: Dr. Becky Kondor

Influenza A(H3N2) summary (1)

Phylogenetics of A(H3N2) HA genes

The vast majority of viruses belonged to one of the J.2 subclades, expressing HA N122D and K276E substitutions.
HA genes have diversified with many subclades:
- J.2.2 — characterized by S124N
- J.2.3 — characterized by N158K, K189R and S378N
- J.2.4 — characterized by T135K (a potential loss of an N-glycosylation site) and K189R
- K — (formerly designated as J.2.4.1) characterized by K2N, S144N (a potential addition of an N-glycosylation site), N158D, I160K, Q173R, T328A and S378N
During this reporting period, subclade K viruses were detected in all regions and predominated in many countries.
There was still circulation of other J.2 subclades, notably J.2 or J.2.3 in South America, J.2.2 or J.2.4 in Africa and Asia.

VCM Information meeting · Slide credit: Dr. Becky Kondor

Influenza A(H3N2) summary (2)

Antigenic characteristics of A(H3N2) viruses

Post-infection ferret antisera raised against cell culture-propagated A/District of Columbia/27/2023-like and egg-propagated A/Croatia/10136RV/2023-like (clade 2a.3a.1, subclade J.2) viruses, representing the A(H3N2) component for the NH 2025-2026 influenza vaccines, showed poor recognition with recently circulating subclade J.2.3 (e.g., A/Netherlands/10685/2024), J.2.4 (e.g., A/Sydney/1359/2024) and K (e.g., A/Darwin/1415/2025) viruses.
Ferret antisera raised against reference viruses from J.2.3 subclades showed good recognition of viruses expressing HA from J.2.3, but poor recognition of other subclades.
Post-infection ferret antisera raised against cell culture-propagated A/Sydney/1359/2024-like and egg-propagated A/Singapore/GP20238/2024-like J.2.4 viruses, representing SH 2026 influenza vaccines, recognised most J.2.4 viruses and many subclade K viruses well.
However, subclade K viruses and J.2.4 viruses with HA substitutions F79V, S144N (addition of a potential N-glycosylation site), N158D, I160K, T328A were better recognised by post-infection ferret antisera raised against cell culture-propagated A/Darwin/1415/2025-like and egg-propagated A/Darwin/1454/2025-like (subclade K) viruses.

VCM Information meeting · Slide credit: Dr. Becky Kondor

Influenza A(H3N2) summary (3)

Human serology studies

Human serology studies were conducted using the serum panels by HI and virus neutralization (VN) assays with recent circulating A(H3N2) viruses with HA genes from subclades J.2, J.2.2, J.2.3, J.2.4, J.2.5 and K.
When compared to titers against cell-propagated A/District of Columbia/27/2023-like vaccine reference viruses, post-vaccination HI GMTs or VN GMTs against many of the recent viruses in all subclades tested were significantly reduced in many serum panels.

Recommendation

The data supported recommending a cell-propagated A/Darwin/1415/2025 (H3N2)-like (K) virus and an egg-propagated A/Darwin/1454/2025 (H3N2)-like (K) virus as the A(H3N2) vaccine antigens for the 2026-2027 northern hemisphere.

VCM Information meeting · Slide credit: Dr. Becky Kondor

The analysis process never stops!

Goal — To create CVVs of emerging subclades for cell-based and egg-based vaccines ahead of Vaccine Consultation Meetings

Prioritization Process

New CVVs are created as needed for each type/subtype
Epidemiologic and Virologic surveillance data drives prioritization

Slide credit: Dr. Becky Kondor

Seasonal Influenza Specimen Shipping Guidelines for CDC

CDC can support up to 4 shipments a year. Please contact InfluenzaVirusSurveillance@cdc.gov to initiate shipments.

Recommended timing of shipments

One shipment ensuring receipt at CDC by December 31, 2025 (coincides with February VCM).
One shipment ensuring receipt at CDC between April and June 2026.
One shipment ensuring receipt at CDC by August 1, 2026 (coincides with September VCM).
One shipment ensuring receipt at CDC between October and November 2026.

Ideal specimens

Influenza positive and SARS-CoV-2 negative original clinical specimens
CT values < 28 for either InfA or InfB
0.5 mL volume
30 recently collected (< 6 weeks)
- 10 A(H1N1)pdm09
- 10 A(H3N2)
- 10 B/Victoria

Reminder — if you have Influenza A Unsubtypeables, immediately contact flusupport@cdc.gov to assist.

Slide credit: Dr. Becky Kondor

Thank you!

CDC Influenza Division · CDC Traveler’s Genomic Surveillance

US Public Health Laboratories

National Influenza Reference Centers
APHL

Global Influenza Surveillance and Response System

National Influenza Centers
WHO CCs / ERL
WHO H5 Ref Labs
University of Cambridge
NextStrain
Previr

Thank you decorative image

We gratefully acknowledge all data contributors, i.e., the Authors and their Originating laboratories responsible for obtaining the specimens, and their Submitting laboratories for generating the genetic sequence and metadata and sharing via the GISAID Initiative, on which this research is based.