Compendium

Immunology Foundations — Biology Reference

33 min read

Immunology Foundations — Biology Reference

Tier-1 reference for the human immune system: innate and adaptive arms, B-cell and T-cell biology, antibody structure and class-switching, MHC restriction and antigen presentation, cytokine networks, vaccine platforms, and the modern (2024-26) immunotherapy stack — checkpoint inhibitors, CAR-T, bispecifics, ADCs, TIL therapy, personalized mRNA cancer vaccines, and engineered TCRs. Cross-links to molecular biology, genetics, biochemistry, pharma process engineering, and protein-design foundation models.

At-a-Glance

  • Two arms, one system. Innate immunity is fast (minutes to hours), germline-encoded, pattern-based, non-specific. Adaptive immunity is slow on first exposure (5-10 d), somatically rearranged, antigen-specific, and produces immunological memory. They are wired together: innate dendritic cells license adaptive T-cell responses; adaptive antibodies arm innate effectors via Fc receptors and complement.
  • Cell census. Adult human carries ~10¹² lymphocytes and ~10¹¹ neutrophils. Bone marrow makes ~10¹¹ neutrophils per day. Thymic T-cell output peaks at age ~1 and decays ~3 %/yr (thymic involution).
  • Specificity arises from rearrangement. V(D)J recombination at TCR and BCR loci by RAG-1/RAG-2 generates ~10¹⁵ theoretical TCR sequences and ~10¹¹ antibody sequences. Negative selection in thymus removes self-reactive T cells; central + peripheral B-cell tolerance prunes auto-reactive B cells.
  • MHC restriction. T-cell receptors recognize peptide fragments presented on Major Histocompatibility Complex (MHC, called HLA in humans). MHC-I (HLA-A/B/C) loads endogenous peptides for CD8⁺ T cells. MHC-II (HLA-DR/DQ/DP) loads exogenous peptides for CD4⁺ T cells. Cross-presentation by cDC1 dendritic cells routes exogenous antigen onto MHC-I.
  • Antibody isotypes. IgM (pentamer, primary response), IgG (4 subclasses, secondary response, crosses placenta), IgA (dimer at mucosa, ~3 g produced per day), IgE (mast-cell arming, allergy and helminths), IgD (B-cell surface marker, function debated).
  • Cytokines wire the network. IFN-α/β anti-viral; IFN-γ macrophage activation and Th1 polarization; IL-2 T-cell proliferation; IL-4 Th2 and B-cell class-switch to IgE; IL-6 acute phase and Th17; IL-10 / TGF-β suppressive; TNF-α inflammatory and a top-5 drug target (Humira).
  • 2024-26 milestones. Lifileucel (TIL therapy) approved Feb 2024 — first solid-tumor cell therapy in metastatic melanoma. Moderna mRNA-4157 + Merck pembrolizumab Phase 3 readout in adjuvant melanoma 2025. Adaptimmune afami-cel (engineered TCR for synovial sarcoma) approved Aug 2024. Casgevy (CRISPR-edited HSC for sickle-cell) launched late 2023, scaling 2025-26. AlphaFold-3 (May 2024) extended structure prediction to antibody-antigen complexes.
  • 2018 Nobel. James Allison (UT MD Anderson, anti-CTLA-4) and Tasuku Honjo (Kyoto, PD-1) — the discovery foundation for checkpoint inhibitors.

Innate Immunity — The Always-On Layer

Cellular components

  • Neutrophils. ~50-70 % of circulating leukocytes; half-life ~8 h in blood, ~1-5 d in tissue. Phagocytose, degranulate (myeloperoxidase, elastase, defensins), release NETs (neutrophil extracellular traps — DNA-protein webs that ensnare pathogens; Brinkmann 2004). Recruited by chemokines IL-8 (CXCL8), LTB₄, and complement C5a.
  • Monocytes / macrophages. Classical CD14⁺⁺CD16⁻ monocytes patrol blood for ~1-3 d, then differentiate to tissue macrophages. Tissue-resident macrophages (Kupffer cells in liver, microglia in brain, alveolar macrophages in lung, Langerhans cells in skin) derive partly from embryonic yolk sac. Polarization: M1 (IFN-γ + LPS → pro-inflammatory, iNOS, TNF-α) vs M2 (IL-4/IL-13 → tissue repair, arginase, anti-inflammatory).
  • Dendritic cells (DCs). Professional antigen-presenting cells (APCs) that bridge innate to adaptive. cDC1 (XCR1⁺, BATF3-dependent) excel at cross-presentation to CD8⁺ T cells; cDC2 (SIRPα⁺) prime CD4⁺ T cells; plasmacytoid DC (pDC) produce massive IFN-α/β to viral infection.
  • Natural killer (NK) cells. Large granular lymphocytes; ~5-15 % of peripheral lymphocytes; lyse cells via perforin/granzyme without prior sensitization. Recognition is “missing self” — KIR (killer immunoglobulin-like receptors) on NK detect loss of MHC-I on stressed or infected cells; NKG2D activating receptor recognizes stress ligands MICA/MICB. ADCC (antibody-dependent cellular cytotoxicity) via FcγRIIIa (CD16) is the basis of rituximab, trastuzumab, and anti-PD1 antibody efficacy.
  • Mast cells, basophils, eosinophils. Granulocyte lineages. Mast cells reside in tissue, arm via FcεRI bound to IgE; degranulate on antigen cross-link releasing histamine, tryptase, leukotrienes — the substrate of acute allergy. Eosinophils combat helminth and drive eosinophilic asthma (target of mepolizumab anti-IL-5, dupilumab anti-IL-4Rα).
  • Innate lymphoid cells (ILCs). ILC1/ILC2/ILC3 mirror Th1/Th2/Th17 cytokine outputs but lack rearranged antigen receptors. Tissue-resident, important in mucosal homeostasis.

Soluble defenses

  • Complement system. ~30 plasma proteins. Three activation paths: classical (antibody-antigen, C1q), lectin (mannose-binding lectin recognizing microbial sugars), alternative (spontaneous C3 tick-over). All converge on C3 convertase → C3b opsonization + C5 convertase → MAC (membrane attack complex C5b-9) → lysis. Anaphylatoxins C3a and C5a recruit phagocytes. Eculizumab (anti-C5, Soliris) treats PNH and aHUS.
  • Antimicrobial peptides. Defensins (α, β, θ), cathelicidins (LL-37), lysozyme, RegIIIγ — direct membrane disruption of microbes.
  • Acute-phase proteins. CRP, SAA, fibrinogen, hepcidin — produced by liver in response to IL-6, IL-1, TNF-α.

Pattern recognition receptors (PRRs)

  • Toll-like receptors (TLRs). 10 functional in humans. Surface TLRs sense bacterial PAMPs (TLR4 → LPS via MD-2/CD14; TLR5 → flagellin; TLR2/1 + TLR2/6 → lipoteichoic acid and lipopeptides). Endosomal TLRs sense nucleic acids (TLR3 → dsRNA; TLR7/8 → ssRNA; TLR9 → unmethylated CpG DNA). Downstream MyD88 / TRIF → NF-κB + IRF transcription of cytokines + type-I interferons.
  • NOD-like receptors (NLRs) and inflammasomes. NOD1/NOD2 sense bacterial peptidoglycan fragments. NLRP3 inflammasome assembles in response to crystals (urate → gout), pore-forming toxins, ATP via P2X7, and mitochondrial damage; activates caspase-1 to cleave pro-IL-1β / pro-IL-18 and gasdermin-D → pyroptosis.
  • RIG-I-like receptors (RLRs). RIG-I + MDA5 sense cytosolic viral RNA (5′-triphosphate or long dsRNA) → MAVS on mitochondria → IRF3/7 → IFN-α/β.
  • cGAS-STING. cGAS senses cytosolic DNA → cyclic GMP-AMP → STING → IRF3 → type-I IFN. Druggable for autoimmunity (STING antagonists) and cancer (STING agonists adjuvant to checkpoint blockade).

Adaptive Immunity — Specificity and Memory

B cells and humoral immunity

B-cell development proceeds in bone marrow: pro-B → pre-B (heavy-chain rearranged) → immature B → naive B in periphery. V(D)J recombination by RAG-1/RAG-2 plus terminal deoxynucleotidyl transferase (TdT) generates BCR diversity. Naive B cells express IgM + IgD on surface.

Activation. T-dependent activation requires antigen via BCR + cognate T-cell help via CD40-CD40L + cytokines. Activated B cells form germinal centers (GC) in lymph node follicles where they undergo:

  • Somatic hypermutation (SHM). AID (activation-induced cytidine deaminase) deaminates C → U in V-region DNA; mutations at ~10⁻³ per bp per division accumulate; high-affinity variants are selected by follicular dendritic cells displaying antigen.
  • Class-switch recombination (CSR). AID-driven recombination at switch (S) regions in IgH locus switches constant region while preserving V(D)J specificity. Direction is cytokine-controlled:
    • IL-4 → IgG1, IgE
    • IFN-γ → IgG2, IgG3
    • TGF-β + IL-5 → IgA
    • IL-21 → IgG1, IgG3

Mature output: plasma cells (antibody factories, can survive decades in bone marrow niches) and memory B cells (rapid recall, isotype-switched, somatically mutated).

Antibody isotypes — structure and function

Antibody = 2 heavy chains + 2 light chains (κ or λ). Fab arms bind antigen via variable domains (V_H, V_L). Fc tail determines effector function.

IsotypeFormHalf-lifeRole
IgMPentamer (J-chain)~5 dFirst responder, complement fixation, agglutination
IgG1Monomer~21 dDominant secondary serum Ab; complement + ADCC + opsonization; crosses placenta
IgG2Monomer~21 dPolysaccharide antigens; weak FcγR engagement
IgG3Monomer~7 dStrongest complement + ADCC; viral response
IgG4Monomer~21 dTolerogenic; Fab-arm exchange; chronic antigen exposure; therapeutic backbone for checkpoint inhibitors
IgA1, IgA2Dimer (J-chain + secretory component)~6 d serumMucosal — gut, lung, breast milk; ~3 g/d secreted
IgEMonomer~2 d serum, weeks on FcεRIHelminth + allergy; mast cell / basophil arming
IgDMonomer~3 dNaive B-cell surface; basophil arming; mucosal IgD

Therapeutic engineering: IgG1 chosen when effector function (ADCC, CDC) is wanted (rituximab anti-CD20). IgG4 chosen when blockade-only is wanted (pembrolizumab anti-PD-1); Fc-silent variants (LALA, N297A) further dampen FcγR engagement.

T cells and cellular immunity

T-cell development in thymus: double-negative (DN1-4) → β-selection (productive TCRβ rearrangement) → double-positive (CD4⁺CD8⁺) → positive selection on cortical thymic epithelial MHC → negative selection on medullary thymic epithelium (AIRE drives ectopic tissue-antigen expression to delete self-reactive clones) → single-positive CD4⁺ or CD8⁺ mature thymocyte. Naive T cells egress via S1P gradient (target of fingolimod in MS).

T-cell receptor (TCR). αβ heterodimer (95 % of T cells) or γδ (5 %). TCR recognizes peptide-MHC complex; CD8 co-receptor binds MHC-I; CD4 co-receptor binds MHC-II. TCR signaling: CD3 complex (γ, δ, ε, ζ) ITAMs phosphorylated by Lck → ZAP-70 → LAT → calcium + Ras + PKC-θ → NFAT, NF-κB, AP-1.

Costimulation. Signal 1 (TCR-pMHC) alone is anergic. Signal 2 from CD28 binding B7 (CD80/CD86) on activated APC drives full activation. Inhibitory: CTLA-4 (outcompetes CD28 for B7, target of ipilimumab) and PD-1 (binds PD-L1/PD-L2, induces SHP-2 phosphatase to dephosphorylate CD28 — target of pembrolizumab, nivolumab).

CD4⁺ helper subsets. Differentiate from naive Th0 by polarizing cytokines and master TFs:

SubsetPolarizersTFSignature cytokinesRole
Th1IL-12, IFN-γT-betIFN-γ, TNF-αIntracellular pathogens, macrophage activation
Th2IL-4GATA-3IL-4, IL-5, IL-13Helminths, allergy
Th17TGF-β + IL-6 + IL-23RORγtIL-17A/F, IL-22Extracellular bacteria + fungi at mucosa; pathogenic in psoriasis, IBD, AS
TfhIL-6, IL-21Bcl-6IL-21Drive germinal-center B-cell help
TregTGF-β + IL-2FoxP3IL-10, TGF-βSuppress self-reactivity; loss → IPEX syndrome

CD8⁺ cytotoxic T cells (CTLs). Kill via perforin (pore-forming) + granzymes (apoptotic proteases), and Fas-FasL engagement. Produce IFN-γ + TNF-α. Memory subsets: T_SCM (stem-cell memory) > T_CM (central memory, lymph-node homing) > T_EM (effector memory, tissue) > T_EFF (terminal effector). T_RM (tissue-resident memory) sits in non-lymphoid tissue (skin, gut, lung) for years.

γδ T cells. Recognize non-peptide antigens — phosphoantigens (Vγ9Vδ2) and lipid-CD1 complexes. Tissue-tropic; bridge innate-adaptive; under development as off-the-shelf cellular therapy (Adicet, Takeda γδ programs).

Mark Davis and the TCR — historical note

Mark Davis (Stanford) cloned the TCR β chain (1984) and α chain (1984), establishing rearranged TCR genes as the basis of T-cell specificity. His lab pioneered tetramer staining (1996, Altman + Davis) — fluorescent MHC-peptide tetramers that directly enumerate antigen-specific T cells, an indispensable assay for vaccine and immunotherapy development.

MHC and Antigen Presentation

MHC class I — endogenous pathway

  • Loci. HLA-A, HLA-B, HLA-C in humans (chromosome 6p21). Each individual carries 2 alleles per locus = up to 6 different class-I molecules. Population polymorphism is extreme: HLA-B has >9,000 alleles.
  • Structure. Heavy chain (α1, α2, α3) + β2-microglobulin. Peptide-binding groove is closed at both ends → accepts 8-11 mer peptides.
  • Processing. Cytosolic proteins are ubiquitinated → degraded by 26S proteasome (immunoproteasome in IFN-γ–activated cells uses β1i/β2i/β5i subunits for better antigenic-peptide generation) → peptides transported into ER by TAP1/TAP2 (target of viral immune evasion — HSV ICP47, HCMV US6) → loaded onto MHC-I via PLC (peptide-loading complex: tapasin, calreticulin, ERp57) → Golgi → surface.
  • Distribution. All nucleated cells (not erythrocytes). Surveys cell interior; viral or tumor peptides flag for CD8⁺ T-cell lysis.

MHC class II — exogenous pathway

  • Loci. HLA-DR, HLA-DQ, HLA-DP.
  • Structure. α + β chains both span membrane. Groove open at both ends → accepts 13-25 mer peptides.
  • Processing. Newly synthesized MHC-II is occupied by invariant chain (Ii / CD74) → trafficked to MIIC late-endosomal compartment → Ii cleaved by cathepsins to CLIP fragment → HLA-DM catalyzes CLIP exchange for endocytosed antigenic peptides → surface.
  • Distribution. Professional APCs only — dendritic cells, macrophages, B cells, thymic epithelium. Inducible on other cells by IFN-γ.

Cross-presentation

cDC1 dendritic cells (XCR1⁺CD141⁺ in humans, CD8α⁺/CD103⁺ in mouse) route exogenous antigen onto MHC-I — essential for CD8⁺ priming against tumors and viruses that do not infect APCs directly. Two proposed routes: vacuolar (limited proteolysis in phagosome with regurgitation onto MHC-I) and cytosolic (Sec61-mediated dislocation into cytosol, proteasomal processing, then ER or back-into-phagosome TAP-dependent loading). Cross-presentation is the cellular substrate of cancer vaccines and tumor immunity.

Antigen-presentation pharmacology

  • HLA matching. Solid-organ transplant (kidney, heart) matches HLA-A/B/DR; stem-cell transplant requires 10/10 or 12/12 match across A/B/C/DR/DQ ± DP.
  • HLA disease associations. HLA-B27 → ankylosing spondylitis; HLA-DRB104:01 → rheumatoid arthritis; HLA-DQ2/DQ8 → celiac; HLA-B57:01 → abacavir hypersensitivity (mandatory pharmacogenomic screen); HLA-B*15:02 → carbamazepine SJS/TEN in East Asians.
  • TCR-mimetic therapeutics. ImmTAC platform (Immunocore) fuses an affinity-matured TCR (recognizing peptide-HLA) to anti-CD3 scFv → redirects polyclonal T cells against HLA-restricted tumor antigens. Tebentafusp (Kimmtrak, anti-gp100/HLA-A*02:01) approved Jan 2022 for uveal melanoma; brenetafusp (PRAME) and others in pipeline.

Cytokines and Chemokines

Soluble protein messengers, typically ~10-30 kDa, that signal via JAK-STAT, MAP-kinase, or NF-κB pathways. Pleiotropic, redundant, and context-dependent — the same cytokine produces different outcomes in different cells.

Interleukins (~40 numbered to date)

  • IL-1α / IL-1β. Pro-inflammatory; IL-1β cleaved from pro-form by caspase-1 in inflammasomes. Anakinra (IL-1Ra), canakinumab (anti-IL-1β) treat CAPS, gout, recurrent pericarditis.
  • IL-2. T-cell growth factor; first recombinant immunotherapy (high-dose Proleukin, 1992 melanoma + RCC). Low-dose IL-2 selectively expands Treg → autoimmune indications (lupus, GVHD). Engineered IL-2 muteins (bempegaldesleukin, nemvaleukin) bias toward CD8/NK over Treg.
  • IL-4 / IL-13. Th2 cytokines, allergy. Dupilumab (Dupixent) blocks IL-4Rα and is the leading biologic in atopic dermatitis, asthma, EoE, COPD with type-2 inflammation, prurigo nodularis. 2024 global sales >$14 B.
  • IL-5. Eosinophil growth/survival. Mepolizumab, reslizumab, benralizumab (anti-IL-5Rα) for eosinophilic asthma + EGPA + HES.
  • IL-6. Acute-phase + Th17 driver. Tocilizumab + sarilumab block IL-6R for RA, GCA, CAR-T cytokine release syndrome (CRS).
  • IL-10. Suppressive; defects → severe early-onset IBD (Glocker 2009).
  • IL-12 / IL-23. Heterodimers sharing p40 (IL-12 p35+p40; IL-23 p19+p40). Ustekinumab (Stelara) anti-p40 — psoriasis, psoriatic arthritis, Crohn’s, UC. Selective IL-23 blockers risankizumab (Skyrizi), guselkumab (Tremfya), tildrakizumab.
  • IL-17. Th17 effector. Secukinumab (Cosentyx), ixekizumab (Taltz), bimekizumab (Bimzelx — also blocks IL-17F, 2023 launch) for psoriasis, AS, PsA.
  • IL-21. Tfh + B-cell + CD8 memory.
  • IL-22. Mucosal repair (epithelial signaling only — receptor on epithelium, not immune cells); barrier protection in gut and skin.

Interferons

  • Type I (IFN-α 13 subtypes, IFN-β). Anti-viral; produced massively by pDCs. Use JAK1/TYK2 → STAT1/STAT2/IRF9 (ISGF3) → ISG transcription. Therapeutic: IFN-β-1a/1b for MS (legacy, displaced by mAbs); IFN-α for hairy cell leukemia, CML (legacy).
  • Type II (IFN-γ). Th1, NK, CD8 source. Macrophage activation, MHC upregulation. Anti-IFN-γ emapalumab for primary HLH.
  • Type III (IFN-λ, IL-29/28A/28B). Epithelial anti-viral, narrower receptor distribution; investigational for hepatitis + respiratory viruses.

TNF family

  • TNF-α. Macrophage + T cell product; binds TNFR1 (apoptosis via DISC) or TNFR2 (survival via NF-κB). Top drug target — adalimumab (Humira, peaked at ~$21 B/yr, now biosimilarized post-2023), infliximab (Remicade), etanercept (Enbrel, soluble TNFR2-Fc), certolizumab, golimumab. Indications: RA, AS, PsA, psoriasis, Crohn’s, UC. Risk: reactivation of latent TB → mandatory IGRA screen.
  • BAFF / APRIL (TNFSF13B / 13). B-cell survival. Belimumab (Benlysta) anti-BAFF for lupus + lupus nephritis.
  • RANKL. Osteoclast differentiation. Denosumab (Prolia / Xgeva) for osteoporosis + bone metastases.

Chemokines

~50 chemokines + ~20 receptors. CXC (CXCL1-17), CC (CCL1-28), C, CX3C. Bind GPCRs to direct leukocyte migration along gradients.

  • CXCL8 (IL-8) → CXCR1/2 → neutrophil recruitment.
  • CCL2 (MCP-1) → CCR2 → monocyte recruitment.
  • CXCL12 (SDF-1) → CXCR4 → HSC homing; plerixafor (Mozobil) mobilizes for transplant. Maraviroc blocks CCR5 in HIV.
  • CCR4 / CCR8 enriched on tumor-infiltrating Treg → targets in oncology (mogamulizumab anti-CCR4 for CTCL).

Humoral vs Cellular Response

AxisHumoralCellular
EffectorAntibodies from plasma cellsCTL killing, macrophage activation
Best againstExtracellular bacteria, toxins, free virusIntracellular pathogens (viruses, mycobacteria), tumors
MemoryLong-lived plasma cells (bone marrow), memory BT_CM, T_EM, T_RM, T_SCM
Vaccine readoutSerum IgG titer, neutralizing AbT-cell ELISpot, intracellular cytokine staining, tetramer
Failure modeHypogammaglobulinemia (XLA, CVID)Combined immunodeficiency (SCID, DiGeorge)

Most real-world infections require both. SARS-CoV-2 immunity is the canonical recent example: neutralizing antibody titers wane in 6-12 months but memory B + T responses persist multi-year and limit severe disease independently of serum titer.

Vaccines

Platforms

  • Live attenuated. MMR, varicella, yellow fever, rotavirus, BCG, oral polio (Sabin), intranasal influenza (FluMist). Best durability and breadth; contraindicated in immunocompromise + pregnancy.
  • Inactivated whole-pathogen. IPV (Salk polio), hepatitis A, rabies, Japanese encephalitis, inactivated influenza, several inactivated COVID vaccines (Sinovac CoronaVac, Sinopharm BBIBP-CorV, Bharat Covaxin).
  • Subunit / protein. Recombinant hepatitis B (yeast-expressed HBsAg, first recombinant vaccine 1986), HPV (Gardasil 9 — L1 VLPs from 9 HPV types), recombinant zoster (Shingrix, gE + AS01 adjuvant — >97 % efficacy), acellular pertussis (DTaP), Novavax NVX-CoV2373 (spike + Matrix-M adjuvant), maternal RSV (Pfizer Abrysvo + GSK Arexvy 2023).
  • Polysaccharide and conjugate. Bacterial capsules (S. pneumoniae, N. meningitidis, H. influenzae b) are T-independent in raw form; conjugation to a protein carrier (CRM197 diphtheria toxoid, tetanus toxoid) recruits T-cell help and confers infant immunogenicity. Pneumococcal: PCV13, PCV15, PCV20 (Prevnar 20). Meningococcal ACWY (Menveo, Menactra), MenB (Bexsero, Trumenba).
  • Toxoid. Tetanus + diphtheria — formaldehyde-inactivated bacterial toxins.
  • Viral-vector. Replication-incompetent adenovirus encoding antigen. Ebola rVSV-ZEBOV (Ervebo, Merck, 2019), ChAdOx1 nCoV-19 (AstraZeneca / Oxford Vaxzevria), Janssen Ad26.COV2.S, Sputnik V (Ad26 + Ad5 prime-boost). Pre-existing anti-vector immunity limits boosting.
  • mRNA-LNP. Linear mRNA encoding antigen, modified with N1-methylpseudouridine (Karikó + Weissman, Nobel 2023) to evade TLR7/8 + MDA5 sensing, capped with anti-reverse cap analog or CleanCap, encapsulated in ionizable lipid nanoparticles (4 lipids: ionizable, helper PC, cholesterol, PEG-lipid). Pfizer-BioNTech BNT162b2 (Comirnaty) and Moderna mRNA-1273 (Spikevax) — first approvals Dec 2020 (EUA), full approval 2021-22. Annual updates 2023, 2024 (XBB.1.5), 2025 (JN.1 / KP.2) seasonal COVID strains. Moderna mRNA-1345 RSV vaccine approved 2024. mRNA flu programs in Phase 3 (Moderna mRNA-1010, Pfizer modRNA flu, Sanofi+Translate Bio).
  • Self-amplifying mRNA (saRNA). Encodes alphavirus replicase that copies itself in cytoplasm. Lower dose, longer expression. Arcturus ARCT-154 (COVID) approved in Japan 2023.

Adjuvants

  • Alum (aluminum hydroxide / phosphate). Workhorse since 1926. NLRP3 + DAMP engagement; favors Th2 / IgG1 in humans.
  • MF59. Squalene-in-water emulsion. Fluad influenza vaccine for elderly.
  • AS01. Liposomal MPL (TLR4 agonist) + QS-21 (saponin from Quillaja). In Shingrix and RTS,S malaria (Mosquirix). Drives potent CD4 Th1 + antibody response.
  • AS03. Squalene emulsion; pandemic flu vaccines.
  • CpG-1018. TLR9 agonist; in Heplisav-B (hep B, 2-dose vs 3-dose Engerix) and Valneva Lyme + chikungunya.
  • Matrix-M. Saponin nanoparticle; Novavax COVID, R21 / Matrix-M malaria (WHO recommended 2023).

Herd immunity and R₀

R₀ (basic reproduction number) = expected secondary cases from one infectious person in a fully susceptible population. Herd immunity threshold ≈ 1 − 1/R₀.

PathogenR₀Threshold
Measles12-1892-95 %
Pertussis12-1792-94 %
Mumps, rubella, smallpox5-780-86 %
Polio5-780-86 %
COVID ancestral2.5-3.560-71 %
COVID Delta5-680-83 %
COVID Omicron BA.18-1087-90 %
Seasonal influenza1.3-1.823-44 %
HIV (untreated MSM)2-550-80 %

Measles is the canonical case for vaccine-coverage mandates — R₀ is high enough that even modest coverage drops cause outbreaks.

Vaccine pipeline highlights (2024-26)

  • Universal influenza candidates targeting HA stalk (Mt Sinai/Florian Krammer) and ferritin-NP (NIH/Masaru Kanekiyo); FluMos-v1 quadrivalent HA-ferritin in Phase 1.
  • HIV mRNA (Moderna + IAVI, gp140 trimer, germline-targeting eOD-GT8 → boost-and-broaden).
  • Universal coronavirus (Walter Reed SpFN with ALFQ adjuvant; mosaic-8 RBD nanoparticle from Caltech).
  • RSV: maternal Abrysvo and 60+ Arexvy + Abrysvo on market 2023; mRNA-1345 (Moderna) approved May 2024.
  • CMV: Moderna mRNA-1647 Phase 3.
  • Lyme: VLA15 (Valneva + Pfizer) Phase 3.
  • Personalized cancer vaccines (see immunotherapy section).

Modern Cancer Immunotherapy

Checkpoint inhibitors — the foundation

Tumors evade immunity by exploiting physiologic T-cell brakes. Blockade releases pre-existing tumor-reactive T cells. Two main axes:

Anti-CTLA-4 (early-priming brake)

  • Ipilimumab (Yervoy, BMS, 2011) — IgG1 anti-CTLA-4. Approved metastatic melanoma, RCC, MSI-H CRC, HCC; high irAE rate.
  • Tremelimumab (Imjudo, AZ) — IgG2 anti-CTLA-4. Approved 2022 with durvalumab in HCC + NSCLC.

Anti-PD-1 / anti-PD-L1 (effector-phase brake)

  • Pembrolizumab (Keytruda, Merck, 2014) — IgG4 anti-PD-1. >40 approved indications; melanoma, NSCLC, HNSCC, MSI-H tumor-agnostic, TMB-H tumor-agnostic, triple-negative breast neoadjuvant, gastric, esophageal, bladder, MCC, cervical, endometrial, RCC + axitinib, HCC + lenvatinib, classical Hodgkin, PMBCL. Global 2024 revenue $29 B+ — top-selling drug worldwide.
  • Nivolumab (Opdivo, BMS) — IgG4 anti-PD-1. Often combined with ipilimumab.
  • Atezolizumab (Tecentriq, Roche) — IgG1 N297A anti-PD-L1.
  • Durvalumab (Imfinzi, AstraZeneca) — anti-PD-L1.
  • Avelumab (Bavencio, Merck KGaA + Pfizer) — anti-PD-L1, ADCC-competent IgG1.
  • Cemiplimab (Libtayo, Regeneron) — anti-PD-1, lead in cutaneous SCC.

Newer axes (2023-26)

  • Anti-LAG-3: relatlimab + nivolumab (Opdualag, BMS, 2022) for melanoma.
  • Anti-TIGIT: tiragolumab (Roche) — Phase 3 mixed.
  • Anti-TIM-3, anti-VISTA, anti-B7-H3 in development.

Allison (CTLA-4) and Honjo (PD-1) shared the 2018 Nobel Prize in Physiology or Medicine. Hallmarks-of-cancer framework (Hanahan + Weinberg 2000, 2011, 2022 update) places “avoiding immune destruction” and “tumor-promoting inflammation” as central enabling characteristics.

CAR-T cell therapy

Autologous T cells engineered ex vivo with a chimeric antigen receptor — extracellular scFv (target binding) + transmembrane + intracellular CD3ζ + costimulatory (CD28 in second-gen, 4-1BB in second-gen, both in third-gen). Lentiviral or retroviral transduction (most products) or CRISPR knock-in (Caribou, Cellectis).

Approved CD19 CAR-T (B-cell malignancies):

  • Tisagenlecleucel (Kymriah, Novartis) — 4-1BB, ALL + DLBCL + FL, approved 2017.
  • Axicabtagene ciloleucel (Yescarta, Gilead/Kite) — CD28, DLBCL + FL.
  • Brexucabtagene autoleucel (Tecartus, Gilead/Kite) — CD28, mantle cell + ALL.
  • Lisocabtagene maraleucel (Breyanzi, BMS) — 4-1BB, DLBCL + FL + CLL/SLL + MCL.

Approved BCMA CAR-T (multiple myeloma):

  • Idecabtagene vicleucel (Abecma, BMS/2seventy) — 4-1BB, 2021.
  • Ciltacabtagene autoleucel (Carvykti, J&J/Legend) — 4-1BB with two BCMA-binding domains, 2022; deepest responses in heavily pretreated myeloma, label expanded to earlier lines 2024.

Toxicities.

  • CRS (cytokine release syndrome). Massive IL-6, IFN-γ, IL-10, TNF-α release; fevers, hypotension, hypoxia. Tocilizumab (anti-IL-6R) is first-line; siltuximab (anti-IL-6) and steroids second-line. ASTCT 2019 grading.
  • ICANS (immune effector cell-associated neurotoxicity syndrome). Encephalopathy, aphasia, seizures, cerebral edema. ICE score for grading. Steroids first-line (tocilizumab does not cross BBB well).
  • Cytopenia, hypogammaglobulinemia, T-cell secondary malignancy (FDA class warning Jan 2024).

2024-26 frontiers. Allogeneic / off-the-shelf CAR-T (Allogene ALLO-501A, Caribou CB-010 with PD-1 knockout, Precision Vor); in-vivo CAR-T (Capstan, Umoja, Orna — lipid nanoparticles delivering CAR mRNA directly to T cells). CAR-T for autoimmunity: Nadir Mahmoud + Georg Schett (Erlangen) drug-free remission in lupus, myositis, scleroderma with CD19 CAR-T (2022-24, NEJM); Kyverna, Cabaletta, Cartesian — Phase 1/2.

Bispecific T-cell engagers (BiTEs / TCEs)

Small recombinant proteins (BiTE: tandem scFv-scFv, ~55 kDa) or full IgG-like bispecifics that bridge a tumor antigen to CD3. Off-the-shelf alternative to CAR-T.

  • Blinatumomab (Blincyto, Amgen) — CD19 × CD3 BiTE, B-ALL, approved 2014. Continuous IV infusion due to short half-life; long-acting follow-on (BiTE-Fc) in development.
  • Teclistamab (Tecvayli, J&J) — BCMA × CD3, multiple myeloma, 2022.
  • Elranatamab (Elrexfio, Pfizer) — BCMA × CD3, 2023.
  • Talquetamab (Talvey, J&J) — GPRC5D × CD3, myeloma, 2023.
  • Mosunetuzumab (Lunsumio, Roche) — CD20 × CD3, FL, 2022.
  • Glofitamab (Columvi, Roche) — CD20 × CD3 (2:1 format), DLBCL, 2023.
  • Epcoritamab (Epkinly, Genmab + AbbVie) — CD20 × CD3, subcutaneous, DLBCL + FL, 2023.
  • Tebentafusp (Kimmtrak, Immunocore) — ImmTAC: TCR (gp100/HLA-A*02:01) × CD3, uveal melanoma, 2022.
  • Tarlatamab (Imdelltra, Amgen) — DLL3 × CD3 BiTE, small-cell lung cancer, approved May 2024 — first major immunotherapy win in SCLC.

Antibody-drug conjugates (ADCs)

mAb tethered to a cytotoxic payload via a cleavable or non-cleavable linker. Antigen binding → internalization → linker cleavage in lysosome → payload release → DNA damage or microtubule poisoning. Bystander effect on antigen-negative neighbors with membrane-permeant payloads.

ADCTargetPayloadIndication
T-DM1 / ado-trastuzumab emtansine (Kadcyla, Roche)HER2DM1 (maytansinoid)HER2⁺ breast
Trastuzumab deruxtecan / T-DXd (Enhertu, Daiichi+AZ)HER2DXd (Topo-I inhibitor)HER2⁺ + HER2-low + HER2-ultralow breast (DB-06 2024), gastric, NSCLC, tumor-agnostic HER2
Sacituzumab govitecan (Trodelvy, Gilead)TROP-2SN-38 (Topo-I)TNBC, HR⁺ breast, UC
Enfortumab vedotin (Padcev, Astellas+Seagen→Pfizer)Nectin-4MMAE (auristatin)Urothelial; + pembrolizumab 1L UC 2023
Brentuximab vedotin (Adcetris)CD30MMAEHodgkin, ALCL
Polatuzumab vedotin (Polivy)CD79bMMAEDLBCL
Datopotamab deruxtecan (Datroway, Daiichi+AZ)TROP-2DXdHR⁺/HER2-low breast Jan 2025
Patritumab deruxtecan (Daiichi+Merck)HER3DXdEGFR-mut NSCLC pending

TIL therapy

Tumor-infiltrating lymphocytes harvested from resected tumor, expanded ex vivo with high-dose IL-2 over ~3-5 weeks, then reinfused after lymphodepleting chemo and supported with IL-2.

  • Lifileucel (Amtagvi, Iovance) — FDA approved 16 Feb 2024 for unresectable/metastatic melanoma after anti-PD-1 — first solid-tumor cell therapy ever approved. ORR ~31 % in heavily pretreated melanoma; durable responses in subset. Steve Rosenberg (NCI) pioneered TIL from the 1980s.
  • Pipeline: TIL in NSCLC, HNSCC, cervical (Iovance LN-145 — accelerated approval expected 2026).

Personalized cancer vaccines

Tumor exome sequencing → neoantigen prediction (peptides arising from somatic mutations + predicted to bind patient HLA) → mRNA-LNP or peptide vaccine encoding ~20-30 top neoantigens.

  • mRNA-4157 / V940 (Moderna + Merck) — individualized neoantigen mRNA, ~34 neoantigens per dose. Phase 2b KEYNOTE-942 (stage III/IV resected melanoma + pembrolizumab vs pembrolizumab alone): 49 % reduction in recurrence or death at 3 yr (presented ASCO 2024). Phase 3 INTerpath-001 melanoma adjuvant ongoing. Additional Phase 2/3 in NSCLC, RCC, MIBC, HNSCC, cutaneous SCC 2024-26.
  • BioNTech BNT122 / autogene cevumeran (BioNTech + Genentech) — Phase 2 in adjuvant melanoma + pancreatic; Sahin / Türeci (Pancreas pilot, 2023 Nature: T-cell responses correlated with delayed recurrence).
  • Geneos GNOS-PV02 — DNA vaccine in HCC, Phase 2 readout.
  • Gritstone GRANITE / SLATE — self-amplifying RNA neoantigen platform.

TCR-engineered T cells

Autologous T cells transduced with a defined αβ TCR recognizing peptide-HLA (vs CAR which is HLA-independent). Targets intracellular antigens (NY-ESO-1, MAGE-A4, PRAME, KRAS-G12).

  • Afamitresgene autoleucel / afami-cel (Tecelra, Adaptimmune) — MAGE-A4 × HLA-A*02:01 TCR-T, approved Aug 2024 for synovial sarcoma — first engineered TCR cell therapy approved.
  • Letetresgene autoleucel (lete-cel, Adaptimmune) — NY-ESO-1 TCR-T, synovial sarcoma + MRCLS, BLA expected 2025.
  • TBio-4101 (TScan), KITE-363/-753 (KRAS), TCR-T programs at Lyell, Neogene, Achilles, T-knife, Medigene.

Recurring engineering motif: CRISPR knock-out of endogenous TCR α + β chains to prevent mispairing; HLA loss-of-function in allogeneic platforms.

Autoimmune Disease and Biologic Therapy

Autoimmunity = failure of central or peripheral tolerance → pathogenic immune attack on self. Mechanisms: autoantibodies (lupus, MG, AIHA), pathogenic T cells (T1D, MS, RA), or both. Diseases cluster on HLA risk haplotypes.

Major diseases and their primary axes

  • Rheumatoid arthritis (RA). Anti-CCP + RF autoantibodies; HLA-DRB1 shared epitope; T-cell + macrophage + synovial fibroblast pathology. TNF-α, IL-6, JAK-STAT druggable.
  • Multiple sclerosis (MS). CD4 + CD8 + B-cell attack on CNS myelin. Anti-CD20 mAbs (ocrelizumab, ofatumumab, ublituximab) dominate disease-modifying landscape; S1P modulators (fingolimod, ozanimod, ponesimod, siponimod); cladribine; natalizumab anti-α4β1.
  • Systemic lupus erythematosus (SLE). Anti-dsDNA, anti-Sm, anti-RNP; type-I IFN signature; immune complex deposition. Belimumab (anti-BAFF), anifrolumab (anti-IFNAR, 2021), voclosporin (calcineurin inhibitor, lupus nephritis), CAR-T (Erlangen, in trials).
  • Inflammatory bowel disease (IBD). Crohn’s + ulcerative colitis. Th1/Th17 axes. Anti-TNF, anti-IL-12/23 (ustekinumab), selective anti-IL-23 (risankizumab, mirikizumab — UC 2023, CD 2025), anti-α4β7 (vedolizumab, gut-selective), JAK inhibitors (tofacitinib, upadacitinib), S1P modulators (etrasimod, ozanimod).
  • Type 1 diabetes (T1D). CD8-mediated β-cell destruction; HLA-DR3/DR4. Teplizumab (Tzield, anti-CD3, Provention/Sanofi, 2022) — first disease-modifying therapy, delays clinical onset ~2 yr in stage-2 T1D.
  • Psoriasis + psoriatic arthritis. Th17 / IL-23 / IL-17 axis. Anti-IL-17A (secukinumab, ixekizumab), anti-IL-17A/F (bimekizumab 2023), anti-IL-23p19 (risankizumab, guselkumab, tildrakizumab).
  • Atopic dermatitis. Th2 + barrier dysfunction. Dupilumab (anti-IL-4Rα) lead biologic; tralokinumab (anti-IL-13); lebrikizumab (2024); JAK inhibitors abrocitinib, upadacitinib.
  • Asthma. Anti-IgE (omalizumab), anti-IL-5/5R (mepolizumab, reslizumab, benralizumab), anti-IL-4Rα (dupilumab), anti-TSLP (tezepelumab — broad asthma 2021).
  • Systemic sclerosis (scleroderma). TGF-β-driven fibrosis. Nintedanib + tocilizumab; rituximab; trials of CD19 CAR-T (Erlangen).
  • ANCA vasculitis. Anti-PR3 or anti-MPO. Rituximab + complement inhibitor avacopan (anti-C5aR, 2021).
  • Myasthenia gravis. Anti-AChR / anti-MuSK. Eculizumab + ravulizumab (anti-C5); efgartigimod (FcRn antagonist, Argenx, 2021) reduces IgG; rozanolixizumab; zilucoplan (C5).

Biologics catalog

  • Anti-TNF. Adalimumab (Humira), infliximab (Remicade), etanercept (Enbrel), certolizumab pegol (Cimzia), golimumab (Simponi).
  • Anti-IL-6/R. Tocilizumab (Actemra), sarilumab (Kevzara).
  • Anti-CD20. Rituximab (Rituxan), ocrelizumab (Ocrevus, MS), ofatumumab (Kesimpta, MS), ublituximab (Briumvi, MS), obinutuzumab (oncology).
  • Anti-IL-23 (p19). Risankizumab (Skyrizi), guselkumab (Tremfya), mirikizumab (Omvoh), tildrakizumab.
  • Anti-IL-12/23 (p40). Ustekinumab (Stelara).
  • Anti-IL-17. Secukinumab (Cosentyx), ixekizumab (Taltz), bimekizumab (Bimzelx).
  • Anti-IL-4Rα. Dupilumab (Dupixent).
  • Anti-IgE. Omalizumab (Xolair).
  • Anti-BAFF. Belimumab (Benlysta).
  • Anti-IFNAR. Anifrolumab (Saphnelo).
  • Anti-α4β7. Vedolizumab (Entyvio).
  • Anti-CD3. Teplizumab (Tzield).
  • FcRn antagonists. Efgartigimod (Vyvgart, Argenx), rozanolixizumab (Rystiggo).
  • JAK inhibitors (small molecule). Tofacitinib (JAK1/3), baricitinib (JAK1/2), upadacitinib (JAK1 — Rinvoq), abrocitinib (JAK1), ruxolitinib (JAK1/2 — also myelofibrosis + topical for vitiligo / AD), deucravacitinib (TYK2 allosteric — Sotyktu psoriasis 2022). FDA boxed warning post-ORAL Surveillance (2021): MACE, malignancy, thrombosis, all-cause mortality vs anti-TNF in RA >50 yr.

Alzheimer’s — adjacent immune-related approvals 2023-24

  • Lecanemab (Leqembi, Eisai + Biogen) — anti-Aβ protofibril mAb, full FDA approval July 2023; slowed cognitive decline ~27 % at 18 mo in Clarity AD.
  • Donanemab (Kisunla, Lilly) — anti-Aβ plaque (modified pyroglutamate epitope), approved July 2024; ~35 % slowing of clinical progression in low/medium tau subgroup of TRAILBLAZER-ALZ 2.
  • ARIA-E + ARIA-H (amyloid-related imaging abnormalities, edema + hemorrhage) are the key class risks; APOE ε4/ε4 highest. These therapies are immunological in mechanism (microglial Fc-mediated plaque clearance) and require IgG1 backbone for ADCC/microglial uptake.

Allergy and IgE Biology

  • Sensitization. Allergen → DC presentation → Th2 polarization → IL-4-driven B-cell class-switch to IgE → IgE binds FcεRI on mast cells + basophils (high-affinity, K_d ~10⁻¹⁰ M, slow off-rate — IgE remains arming the cells for weeks).
  • Effector phase. Allergen re-exposure cross-links surface IgE → mast-cell degranulation: histamine, tryptase, chymase, heparin (preformed) + leukotrienes LTC4/D4/E4, PGD2, PAF, IL-4, IL-13, TNF-α (newly synthesized).
  • Anaphylaxis. Systemic mast-cell degranulation → vasodilation, capillary leak, bronchoconstriction. Epinephrine IM (0.3-0.5 mg adult, 0.15 mg pediatric, EpiPen / Auvi-Q / generic) is the only proven first-line therapy; antihistamines and steroids are adjuncts only. Neffy (epinephrine nasal spray, ARS Pharma) approved Aug 2024 — first needle-free option.
  • Therapeutics.
    • Omalizumab (Xolair) — anti-IgE mAb, depletes free IgE, downregulates FcεRI. Indications: allergic asthma, chronic spontaneous urticaria, nasal polyps, and food allergy (Feb 2024 approval) — reduces reaction severity to inadvertent exposure.
    • Dupilumab (Dupixent) — anti-IL-4Rα; type-2 disease across asthma, AD, EoE, CRSwNP, COPD with type-2 inflammation, prurigo nodularis.
    • Tezepelumab (Tezspire) — anti-TSLP, severe asthma irrespective of eosinophil phenotype.
  • Allergen-specific immunotherapy (AIT). Subcutaneous (SCIT) since 1911 or sublingual (SLIT — Grastek timothy, Ragwitex ragweed, Odactra HDM, Palforzia peanut OIT 2020). Mechanism: induction of allergen-specific IgG4 blocking antibodies + IL-10⁺ Treg + iTreg deviation away from Th2.

Transplant Immunology

HLA matching

  • Solid organ. Kidney: ABO + HLA-A/B/DR matching desirable; crossmatch (donor-specific antibodies) mandatory. Heart, liver: ABO matching usually sufficient; liver is most immunoprivileged.
  • HSCT (bone marrow / stem cell). Match at HLA-A/B/C/DR/DQ (10/10) or with DP (12/12). Haploidentical with post-transplant cyclophosphamide (PTCy, Luznik / Johns Hopkins) has expanded donor pool dramatically since 2008.

Rejection axes

  • Hyperacute rejection. Pre-formed donor-specific antibodies → minutes to hours; abolished by crossmatch.
  • Acute cellular rejection. Donor-reactive T cells; days to weeks.
  • Acute antibody-mediated rejection (AMR). De novo DSA + complement deposition.
  • Chronic rejection. Vasculopathy + interstitial fibrosis; multifactorial.

Immunosuppression

  • Induction. Anti-thymocyte globulin (rabbit ATG), basiliximab (anti-CD25), alemtuzumab (anti-CD52).
  • Calcineurin inhibitors (CNI). Tacrolimus (FK506), cyclosporine. Block IL-2 transcription via NFAT dephosphorylation. Nephrotoxic.
  • mTOR inhibitors. Sirolimus, everolimus. Block IL-2 signaling and proliferation.
  • Antimetabolites. Mycophenolate mofetil (MMF / Cellcept) — IMPDH2 → blocks GTP synthesis selectively in lymphocytes; azathioprine.
  • Steroids. Prednisone, methylprednisolone.
  • Costimulation blockade. Belatacept (Nulojix) — CTLA-4-Ig that blocks CD28-B7 — kidney transplant alternative to CNI; avoids nephrotoxicity.

Xenotransplantation — 2022-26 status

Decades of work on porcine donors gated by hyperacute rejection (anti-Gal α-1,3-Gal antibodies in humans), acute vascular rejection, and porcine endogenous retroviruses (PERV). Revivicor (United Therapeutics) and eGenesis (Harvard / Church lab) produce gene-edited pig donors with up to 10-69 CRISPR edits: GGTA1 / B4GALNT2 / CMAH knockouts (xenoantigens), PERV inactivation, and human transgenes for CD46, CD55 (complement regulators), CD47 (don’t-eat-me), thrombomodulin, EPCR, HO-1.

  • David Bennett Sr., Jan 2022, University of Maryland. First pig-to-human heart transplant from 10-edit Revivicor donor; lived 60 d, died of capillary congestion attributed in part to porcine CMV reactivation. (Often misattributed in popular reporting — Bartley Griffith was the lead surgeon.)
  • Lawrence Faucette, Sep 2023, U Maryland. Second pig-heart recipient; lived ~40 d.
  • Richard Slayman, March 2024, Massachusetts General Hospital. First pig-kidney transplant in a living human, 69-edit eGenesis donor. Survived ~2 mo.
  • Lisa Pisano, April 2024, NYU Langone. Pig-kidney transplant alongside mechanical heart pump.
  • Towana Looney, Nov 2024, NYU Langone / U Alabama Birmingham (UAB). 10-edit Revivicor pig kidney; longest-surviving xenotransplant recipient — discharged home in early 2025.
  • Tim Andrews, Jan 2025, Mass General. Second living-human pig kidney recipient.

The clinical-trial pathway (United Therapeutics UKidney, eGenesis EGEN-2784) opened in 2024-25 under FDA IDE; small Phase 1 trials are accruing.

Specific Infectious-Disease Vaccines

HIV

No approved vaccine. Challenges: extreme env glycoprotein variability, glycan shield, integration into host genome, rapid escape. Major lines: broadly neutralizing antibody (bnAb) passive infusion (VRC01, 3BNC117, 10-1074); germline-targeting eOD-GT8 → boost-and-broaden mRNA (IAVI + Moderna, Phase 1 2022-25); mosaic vector (Janssen Ad26.Mos4.HIV — Mosaico stopped Jan 2023 for futility); HIV cure programs use shock-and-kill or block-and-lock strategies.

COVID-19

mRNA (Pfizer/BNT BNT162b2, Moderna mRNA-1273), viral vector (Janssen Ad26.COV2.S, AZ ChAdOx1), inactivated (Sinovac, Sinopharm), subunit (Novavax NVX-CoV2373), recombinant in Cuba (Soberana). Annual seasonal updates 2023 (XBB.1.5), 2024 (KP.2 / JN.1 lineage), 2025 (LP.8.1 / KP.3.1.1). Monoclonal Ab prophylaxis: tixagevimab + cilgavimab (Evusheld, withdrawn after Omicron escape), sotrovimab (limited after JN.1), pemivibart (Pemgarda, Invivyd, 2024) — current standard for immunocompromised.

Influenza

Annual quadrivalent (2 A: H1N1 + H3N2; 2 B: Yamagata + Victoria; B Yamagata dropped from 2024-25 formulations after presumed extinction post-COVID). High-dose (Fluzone HD), adjuvanted (Fluad MF59), recombinant (Flublok), live attenuated nasal (FluMist — self-administered approval 2024). Universal-flu candidates targeting HA stem or conserved internal proteins (M1, NP) ongoing.

mRNA-LNP platform — design notes

  • Modified nucleosides (m1Ψ, N1-methylpseudouridine) replace uridine to evade PRR sensing.
  • 5′ cap (CleanCap AG / m7G) for translation.
  • 5′ + 3′ UTRs optimized for stability (Moderna proprietary UTRs; BioNTech alpha-globin / 3′ tail).
  • PolyA tail ~100-120 nt.
  • LNP = ionizable lipid (Pfizer ALC-0315, Moderna SM-102) + DSPC + cholesterol + PEG-DMG. Ionizable amine charges at low endosomal pH → endosomal escape.
  • Cold-chain. -80 °C / -20 °C originally; reformulated lyophilized + 2-8 °C versions in development for second-generation products.

Gene-Edited Immune Therapy

Casgevy (exa-cel) — first approved CRISPR therapy

  • Vertex + CRISPR Therapeutics. Autologous CD34⁺ HSC edited ex vivo at BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF), bypassing the sickle / β-thal defect in adult HbB.
  • FDA approval 8 Dec 2023 (sickle cell disease) and 16 Jan 2024 (transfusion-dependent β-thalassemia). UK MHRA approval 16 Nov 2023 — first regulatory approval of a CRISPR therapy globally.
  • Clinical readouts ASH 2023/2024: vast majority of treated SCD patients VOC-free; β-thal patients transfusion-independent. Mechanism: lentiviral-free, Cas9 RNP electroporation.
  • Process: HSC mobilization with plerixafor (G-CSF contraindicated in SCD) → apheresis → CRISPR edit → cryopreserve → myeloablative busulfan conditioning → infuse.
  • Scale-up bottlenecks: ~50 authorized treatment centers worldwide as of 2025; throughput limited by apheresis + conditioning + bed-availability rather than cell-product manufacturing.

Other gene-edited immune programs

  • Lyfgenia (bluebird bio). Lentiviral β-globin gene-addition for SCD, FDA approved same day as Casgevy.
  • PBCAR0191 / CB-010 / CTX110 / 112 / 130. Allogeneic CD19 or CD70 CAR-T with TCR + B2M + PD-1 multiplex KO; safety + variable efficacy across Allogene, Caribou, CRISPR Therapeutics.
  • CTX320 / NTLA-2002. In-vivo LNP-CRISPR for hereditary angioedema (Intellia, KLKB1 KO) — Phase 3 ongoing 2025.
  • Verve VERVE-102. In-vivo base editing PCSK9 — Phase 1b 2024.

AI for Immunology

TCR–antigen prediction

  • NetMHCpan, NetMHCIIpan (DTU). ANN/transformer pan-allele MHC-peptide binding predictors. NetMHCpan-4.1 still the most-used clinical-grade tool for predicting neoantigen presentation.
  • MHCflurry, MixMHCpred, PRIME, BigMHC — alternative + ensemble approaches.
  • TCR repertoire analysis. Immunarch, Adaptive Biotechnologies immunoSEQ, MiXCR for V(D)J assembly; GLIPH/2, TCRdist3, DeepTCR for clustering by specificity; TCRen, ERGO, NetTCR, pMTnet for pMHC-TCR pairing prediction. Dramatic improvement expected from large transformer models trained on Adaptive’s billions of clonotypes + curated MIRA / VDJdb / IEDB datasets.
  • Repertoire. AIRR Community + iReceptor + OAS (Observed Antibody Space, Oxford) — public corpora used to pretrain TCR/BCR language models (TCR-BERT, AbLang, IgLM, ESM-IF, ProtBERT-BFD).

Structure-prediction for antibodies and TCRs

  • AlphaFold-2 (DeepMind, 2021) — backbone protein structure; less reliable for CDR-H3 antibody loops + TCR-pMHC interfaces.
  • AlphaFold-3 (Google DeepMind + Isomorphic Labs, May 2024) — extends to antibody-antigen, protein-ligand, protein-nucleic acid complexes; meaningful improvements in immune-complex prediction with proper sampling.
  • ESM-3 / ESM-Cambrian (EvolutionaryScale, 2024). Multimodal protein language models with sequence + structure + function tokens.
  • RoseTTAFold (Baker lab) + diffusion-based RFdiffusion / RFdiffusion-AA — de novo binder design and antibody scaffold generation.

Antibody and binder design — companies

  • Profluent Bio. Protein language models (ProGen / OpenCRISPR); de novo CRISPR enzymes and antibody design.
  • Generate Biomedicines. Chroma diffusion-model platform for antibodies + biologics; pipeline in oncology + infectious disease + immunology (GB-0669 anti-CMV, GB-0895 IL-2 mimetic).
  • Absci. Reverse Mol-to-Lab integrated de novo antibody design + wet-lab generation.
  • Xaira Therapeutics (2024). $1B launch from ARCH + Foresite; foundation models for immunology + drug discovery.
  • Latent Labs (2024). Simon Kohl (ex-DeepMind AF2 lead) — protein design startup.
  • Isomorphic Labs (Alphabet). AlphaFold-3 spin-out drug discovery with Novartis + Lilly deals (2024).
  • EvolutionaryScale. ESM-3 / Cambrian; commercial protein design API.

AI in immunology — selected pipelines

  • Repertoire diagnostics. Adaptive + Microsoft ImmuneCODE / T-Detect (T-cell-based COVID + Lyme + cancer detection).
  • Vaccine design. Moderna + IBM mRNA-LNP design; CytoReason + Pfizer / Sanofi disease-graph models for biologic indication expansion.
  • Neoantigen prediction. Personalis NEXT Personal, Genentech AVANCE, Moderna mRNA-4157 pipeline rely on integrated ML stacks predicting expression × processing × MHC binding × clonality × TCR responsiveness.

See transformer-architecture for the underlying model architecture and bioinstrumentation for the wet-lab platforms producing training data.

Microbiome and Immunity

  • Gut microbiome. ~10¹³ bacteria; ~150-200 species per individual; communities cluster into “enterotypes.” Train mucosal IgA, Treg (clostridia clusters IV + XIVa → butyrate → Treg differentiation), Th17 (segmented filamentous bacteria in mouse), and barrier integrity.
  • Disease links. Dysbiosis associated with IBD, T1D, asthma + atopy (“hygiene hypothesis”), colorectal cancer (Fusobacterium nucleatum), and even response to checkpoint inhibitors (Akkermansia muciniphila + Faecalibacterium prausnitzii enrichment correlates with anti-PD-1 response — Routy + Zitvogel 2018, Gopalakrishnan + Wargo 2018).
  • Therapeutics. Fecal microbiota transplant approved products: Rebyota (Ferring, 2022) + Vowst (Seres, 2023, oral) for recurrent C. difficile. Live biotherapeutic pipeline (Vedanta, Finch, Pendulum). FMT or defined consortia adjunct to checkpoint inhibitors in melanoma (Phase 2).

Immune Aging (Immunosenescence)

  • Thymic involution. Thymus active output drops sharply after puberty; naive T-cell pool maintained by peripheral homeostatic proliferation, losing diversity.
  • Inflammaging. Chronic low-grade IL-6, TNF-α, CRP elevation contributes to age-related comorbidity (CV disease, frailty, cognitive decline). CHIP (clonal hematopoiesis of indeterminate potential — somatic DNMT3A, TET2, ASXL1 in HSC) drives this in elderly populations and is a CV risk factor independent of LDL.
  • Vaccine response. Reduced antibody titers and durability in elderly; Shingrix + AS01 + high-dose flu address this gap.
  • CMV imprint. Chronic CMV expands and exhausts CD8⁺ T-cell compartment; in CMV-positive elderly, ~10-50 % of CD8 repertoire can be CMV-specific.
  • Senolytic + senomorphic strategies. Dasatinib + quercetin, fisetin, navitoclax — Phase 1/2 trials in aging-related conditions.

Cross-References

  • cell-molecular-biology — signal transduction, gene expression, protein trafficking that underlie cytokine signaling, MHC processing, and B/T cell activation.
  • genetics-and-genomics — V(D)J recombination, somatic hypermutation, HLA polymorphism, GWAS for autoimmune disease, and tumor mutational burden.
  • neuroscience-foundations — neuroinflammation, microglia, MS, Alzheimer’s amyloid clearance by anti-Aβ antibodies.
  • biochemistry-foundations — enzyme catalysis (caspases, proteasome, proteases), protein folding, glycosylation, lipid biology relevant to LNPs.
  • pharma-process-engineering — biologic manufacturing (mAb CHO production, mRNA in-vitro transcription, LNP formulation, CAR-T autologous workflow, viral-vector production).
  • bioinstrumentation — flow cytometry, mass cytometry (CyTOF), single-cell RNA-seq, sequencers underlying TCR/BCR repertoire profiling, FACS sorting for cell-therapy QC.
  • transformer-architecture — foundation models for protein and TCR/BCR sequence + structure.

Citations and Key References

  • Janeway’s Immunobiology, Murphy + Weaver, 10th ed., 2022 — standard reference textbook.
  • Abbas, Lichtman, Pillai, Cellular and Molecular Immunology, 10th ed., 2022.
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  • Polack FP et al. Safety and efficacy of BNT162b2 mRNA Covid-19 vaccine. NEJM 383, 2603 (2020); Baden LR et al. Moderna mRNA-1273 efficacy. NEJM 384, 403 (2021).
  • Sahin U, Türeci Ö et al. Individualized neoantigen vaccines for pancreatic cancer (autogene cevumeran). Nature 618, 144 (2023).
  • Khattak A et al. mRNA-4157 + pembrolizumab (KEYNOTE-942 Phase 2b melanoma). Lancet 403, 632 (2024).
  • Iovance lifileucel — FDA approval announcement 16 Feb 2024; Sarnaik AA et al. Lifileucel in unresectable melanoma. J Clin Oncol 2021.
  • Frangoul H, Locatelli F et al. CRISPR-Cas9 gene editing for sickle cell + β-thalassemia. NEJM 384, 252 (2021) — exa-cel pivotal data.
  • Mackensen A, Müller F, Mougiakakos D, Schett G et al. Anti-CD19 CAR-T in lupus. Nature Med 28, 2124 (2022); follow-on multi-disease autoimmune cohort, NEJM 2024.
  • Griffith BP, Bartley P, Mohiuddin MM et al. Genetically modified porcine-to-human cardiac xenotransplantation (David Bennett). NEJM 387, 35 (2022).
  • Williams WB, Wiehe K et al. Initiation of HIV neutralizing-antibody lineage in humans via germline-targeting (eOD-GT8). Cell 2024.
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  • Routy B, Zitvogel L et al. Gut microbiome influences anti-PD-1 response. Science 359, 91 (2018); Gopalakrishnan V, Wargo JA et al. Gut microbiome modulates response to anti-PD-1 in melanoma. Science 359, 97 (2018).
  • Brinkmann V et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532 (2004).
  • IEDB.org, VDJdb.cdr3.net, OAS (opig.stats.ox.ac.uk/webapps/oas/) — public immune-repertoire and epitope databases.

End — Immunology Foundations, Tier-1 reference.

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