Therapeutic vaccines

Definition and Clinical Objective
Therapeutic vaccines are biologically active immunological preparations designed to stimulate or modulate the immune system to target and control existing diseases, rather than preventing them (as with prophylactic vaccines). Unlike traditional vaccines, which are primarily used to prevent infectious diseases, therapeutic vaccines are developed to treat conditions such as chronic infections, cancer, and autoimmune diseases by enhancing the host's immune response to specific antigens.

They aim to:

• Elicit or boost an antigen-specific immune response (T-cell and/or antibody-mediated)

• Modify immune tolerance or suppression

• Induce immunological memory to prevent disease progression or recurrence

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Mechanism of Action

Therapeutic vaccines work via different mechanisms depending on the disease and target antigen. General mechanisms include:

1. Antigen presentation: Delivering a disease-specific antigen to antigen-presenting cells (APCs), especially dendritic cells, to elicit adaptive immunity.

2. Cellular immunity: Activation of cytotoxic CD8⁺ T-cells to recognize and destroy diseased cells (e.g., cancer, virally infected).

3. Humoral immunity: Inducing antibody production to neutralize pathogens or abnormal cells.

4. Immune modulation: Rebalancing immune responses (e.g., shifting Th1/Th2 balance or suppressing regulatory T cells in cancer).

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Categories of Therapeutic Vaccines

Type	Description
Cancer vaccines	Target tumor-associated or tumor-specific antigens
Infectious disease vaccines	Enhance immunity in chronic infections (e.g., HIV, HBV, TB)
Autoimmune disease vaccines	Modify immune tolerance (e.g., Type 1 diabetes, rheumatoid arthritis)
Allergy vaccines	Induce desensitization (e.g., allergen-specific immunotherapy)
Neurodegenerative vaccines	Experimental; target misfolded proteins (e.g., Alzheimer’s β-amyloid)

Approved and Investigational Therapeutic Vaccines

1. Cancer Therapeutic Vaccines

Vaccine	Target Disease	Status
Sipuleucel-T (Provenge)	Prostate cancer (mCRPC)	FDA-approved
Talimogene laherparepvec (T-VEC)	Advanced melanoma	FDA-approved (oncolytic virus)
CimaVax-EGF	Non-small cell lung cancer (NSCLC)	Approved in Cuba, clinical trials elsewhere
VGX-3100	Cervical intraepithelial neoplasia (HPV 16/18)	Phase 3
IMA901, GVAX, PANVAC	Renal cell carcinoma, pancreatic, breast	Phase 1–2
MAGE-A3 vaccine	NSCLC, melanoma	Trials discontinued (no efficacy)

2. Infectious Disease Therapeutic Vaccines

Vaccine Candidate	Target Pathogen	Status
NASVAC	Hepatitis B (therapeutic)	Phase 3 (Bangladesh)
Tat vaccine	HIV (targets viral protein Tat)	Clinical trials
TheraVac	Hepatitis B (HBV)	Preclinical/early clinical
Mycobacterium vaccae	Tuberculosis (adjuvant therapy)	Investigational

3. Autoimmune and Allergy Therapeutic Vaccines

Vaccine/Approach	Target Disease	Status
Rheumavax	Rheumatoid arthritis (RA)	Phase 1–2
BHT-3021 (proinsulin DNA)	Type 1 diabetes	Phase 2
Allergen-specific immunotherapy	Allergic rhinitis, asthma	Approved (e.g., SCIT/SLIT)

4. Neurological Disease Vaccines (Experimental)

Vaccine Name	Target Protein	Target Disease
CAD106, UB-311	β-amyloid	Alzheimer’s disease
ACI-35, AADvac1	Tau protein	Alzheimer’s disease
PD01A/PD03A	α-synuclein	Parkinson’s disease

Formulations and Platforms

• Peptide-based vaccines

• DNA or mRNA vaccines

• Dendritic cell vaccines (e.g., Sipuleucel-T)

• Oncolytic virus vaccines (e.g., T-VEC)

• Virus-like particles (VLPs)

• Whole-cell tumor vaccines

• Protein-subunit vaccines

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Adverse Effects

Therapeutic vaccines generally have favorable safety profiles, but adverse effects can include:

• Injection-site reactions (redness, swelling, pain)

• Flu-like symptoms (fever, chills, fatigue)

• Autoimmunity exacerbation (especially in autoimmune-targeted therapies)

• Cytokine release syndrome (rare, mainly in cancer immunotherapy)

• Anaphylaxis (rare but serious)

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Contraindications

• Severe immunosuppression (e.g., advanced AIDS, chemotherapy)

• Known hypersensitivity to vaccine components

• Autoimmune flare during acute phase (specific to autoimmune vaccines)

• Pregnancy and lactation – dependent on specific vaccine; most are not studied or not advised

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Precautions

• Monitor for immune-related adverse events (irAEs), especially in cancer vaccines

• Evaluate autoimmune markers prior to administration in susceptible individuals

• Consider combination with immune checkpoint inhibitors to optimize efficacy in oncology

• Therapeutic vaccines are often part of multimodal treatment regimens, not standalone solutions

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Drug and Biologic Interactions

• Checkpoint inhibitors (e.g., nivolumab, pembrolizumab): Synergistic immune response

• Immunosuppressants: May reduce efficacy of therapeutic vaccines

• Corticosteroids: Blunt immune response if given concurrently or soon after vaccination

• Antibiotics/antivirals: May interfere with oncolytic or live-attenuated vaccine platforms

• Chemotherapeutics: Timing is critical to preserve immune responsiveness

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Immunological Considerations

• Requires functional dendritic cells, T-cells, and/or B-cells

• Must overcome immune evasion mechanisms in cancer and chronic infections

• Tumor microenvironment suppression often limits efficacy of cancer vaccines

• Immune checkpoint blockade (e.g., anti-PD-1) enhances vaccine efficacy in tumors

• Adjuvants are critical for improving immunogenicity (e.g., TLR agonists)

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Regulatory and Clinical Status

• FDA and EMA have approved only a few therapeutic vaccines (e.g., Provenge, T-VEC)

• Many are in Phase I/II trials

• Approval challenges include:

  • Variability in immune responses

  • Disease-specific biomarkers and endpoints

  • Manufacturing complexity (e.g., autologous cell therapies)

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Advantages

• Potential to provide long-lasting disease control via immune memory

• May delay or reduce recurrence of chronic disease or cancer

• Can reduce pathogen burden in chronic infections

• Can induce specific immune responses with fewer systemic effects

• Potential to modify disease course in autoimmune and neurodegenerative diseases

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Limitations

• Efficacy varies depending on immune status and disease stage

• Require sophisticated delivery and manufacturing systems

• Not universally effective across all tumor types or chronic infections

• Immune escape mechanisms limit responses in some patients

• Often require multiple doses or boosters

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Monitoring and Evaluation

• Monitor immune biomarkers (e.g., IFN-γ, T-cell subsets)

• Disease-specific indicators:

  • PSA levels in prostate cancer

  • Viral load in HIV/HBV

  • Lesion regression in HPV-associated neoplasia

• Use of imaging (e.g., PET/CT scans) in cancer settings

• Biopsy and histological evaluation for immunological infiltration

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Notable Examples and Case Studies

1. Sipuleucel-T (Provenge)

   • First FDA-approved therapeutic cancer vaccine

   • Autologous dendritic cells exposed to prostate cancer antigen (PAP) + GM-CSF

   • Used in metastatic castration-resistant prostate cancer (mCRPC)

   • Prolonged survival by ~4 months in pivotal IMPACT trial

2. Talimogene laherparepvec (T-VEC)

   • Modified herpes simplex virus encoding GM-CSF

   • Injected intratumorally to lyse cancer cells and stimulate immune response

   • Used in advanced melanoma

3. VGX-3100

   • DNA vaccine targeting HPV16/18 E6 and E7 oncogenes

   • For cervical precancerous lesions

   • Administered via intramuscular electroporation

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Research Directions

• mRNA-based therapeutic vaccines (building on COVID-19 platform success)

• Neoantigen personalization: patient-specific tumor antigen discovery

• Combination with immune checkpoint blockade for synergy

• Nanoparticle-based vaccine delivery systems

• B-cell epitope-targeted therapeutic vaccines

• TCR-based and dendritic-cell vaccine platforms