Vaccines and Therapies

The history of infectious disease is largely a history of mortality. Smallpox killed 300 million people in the 20th century alone. Polio paralyzed hundreds of thousands annually. HIV has killed ~40 million since the epidemic began. The tools that have addressed these diseases — vaccines and antivirals — represent the direct translation of virology and immunology into life-saving interventions. And the current generation of immune-based therapies for cancer follows the same conceptual logic.

Understanding vaccines and therapies isn't optional background knowledge for computational biologists — it's directly relevant to the data you'll encounter: vaccine immunogenicity trials, antiviral resistance surveillance, clinical trial endpoints, and the computational pipeline that enables personalized cancer immunotherapy.

Vaccine Principles: Training the Immune System

All vaccines operate on the same principle: expose the immune system to antigens from a pathogen in a context that generates immunological memory, without causing disease. On subsequent encounter with the real pathogen, memory B and T cells respond rapidly and vigorously.

The key variables in vaccine design are:

1. Which antigen(s) to present — ideally neutralizing epitopes, conserved across variants
2. In what form — live attenuated, inactivated, protein subunit, nucleic acid
3. With what adjuvant — ingredients that enhance immunogenicity by activating innate immunity
4. Via what route — intramuscular, intranasal, oral (affects the type of immune response)

Vaccine Types

Live attenuated vaccines contain a weakened form of the pathogen that replicates but doesn't cause disease. They generate robust, long-lasting immunity because the attenuated virus goes through its full replication cycle, producing all viral antigens and activating both T and B cell responses.

Examples: MMR (measles-mumps-rubella), varicella, yellow fever, OPV (oral polio vaccine).

Limitation: can rarely revert to virulence (OPV → vaccine-derived poliovirus in under-vaccinated populations); contraindicated in immunocompromised individuals.

Inactivated vaccines contain killed pathogen — unable to replicate. Safer than live attenuated; require adjuvant for immunogenicity; often require booster doses.

Examples: IPV (inactivated polio vaccine), influenza (most formulations), hepatitis A, whole-cell COVID vaccines (CoronaVac, Covaxin).

Protein subunit vaccines contain specific purified proteins from the pathogen. Very safe; require adjuvant and boosters; can select the most immunogenic, neutralizing targets.

Examples: Hepatitis B surface antigen (HBsAg), HPV L1 protein (Gardasil), pertussis toxoid (in Tdap), recombinant shingles vaccine (Shingrix).

mRNA vaccines contain lipid nanoparticle-encapsulated mRNA encoding a viral antigen. The mRNA is taken up by cells, translated into antigen, which activates T and B cells. The mRNA is degraded within days; no viral DNA ever enters the nucleus; no integration possible.

Advantages: rapid development (days from sequence to design); highly scalable production; no cell culture of virus required; easily adaptable to new variants.

The Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) COVID-19 vaccines demonstrated ~90% efficacy against the original strain — the highest efficacy ever achieved for a respiratory virus vaccine, and achieved in under 12 months from sequence to authorization.

Viral vector vaccines use a harmless virus (adenovirus, vaccinia) engineered to carry a gene encoding the pathogen's antigen. The vector infects cells, produces the antigen, and activates immunity.

Examples: Oxford-AstraZeneca COVID-19 (ChAdOx1), Johnson & Johnson (Ad26), Ebola vaccine (rVSV-ZEBOV).

Adjuvants

Adjuvants enhance vaccine immunogenicity by activating innate immune signals that provide the "danger signal" needed for full adaptive immune activation. Without adjuvant, protein subunit vaccines generate weak, short-lived responses.

Common adjuvants:

• Alum (aluminum hydroxide/phosphate): oldest and most common; activates NLRP3 inflammasome; biases toward Th2 responses
• AS01B (in Shingrix): liposome + MPL + QS-21; activates TLR4 and cytoplasmic receptors; drives strong CD4+ T cell and antibody responses
• AS04 (in Cervarix): alum + MPL; activates TLR4
• CpG 1018 (in Heplisav-B): TLR9 agonist; strong B cell activation

The choice of adjuvant shapes the character of the immune response — Th1 vs. Th2 bias, CD4 vs. CD8 T cell responses, IgG vs. IgA antibodies.

Antiviral Drugs: Targeting Viral Biology

Unlike antibiotics, which can target bacterial-specific structures (cell walls, ribosomes), antivirals must target the few viral-specific components while leaving host cell machinery intact.

HIV Antiretroviral Therapy (ART)

Modern ART suppresses viral replication to undetectable levels, preventing AIDS and blocking transmission. Multiple drug classes target different steps:

Standard first-line ART is 2 NRTIs + 1 INSTI. Dolutegravir-based regimens are now WHO-recommended globally due to high efficacy, low side effects, and high barrier to resistance.

Direct-Acting Antivirals (DAAs) for Hepatitis C

Before 2011, HCV treatment required pegylated interferon-α + ribavirin — toxic, poorly tolerated, ~50% cure rate. The discovery of NS5B (polymerase) inhibitors, NS5A inhibitors, and NS3/4A protease inhibitors, and their combination into all-oral regimens, transformed HCV treatment:

Modern DAA combinations (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) achieve >95% cure rates in 8–12 weeks, across all HCV genotypes, with minimal side effects. This is one of the greatest successes in infectious disease pharmacology — a chronic viral infection with no cure became curable in a decade.

SARS-CoV-2 Therapeutics

Nirmatrelvir/ritonavir (Paxlovid): A protease inhibitor targeting the Mpro (main protease) of SARS-CoV-2, co-dosed with ritonavir (a pharmacokinetic booster). ~90% reduction in hospitalization when taken early. Ritonavir inhibits CYP3A4, increasing nirmatrelvir plasma levels but also causing significant drug-drug interactions.

Remdesivir: An adenosine nucleotide analogue that inhibits RdRp. Given IV; modest benefit when given early in hospitalized patients.

Molnupiravir: An RdRp inhibitor that works by causing catastrophic hypermutation in the viral genome. Concerns about mutagenesis in host cells limited its use; lower efficacy than Paxlovid.

Monoclonal Antibodies: Targeted Immunotherapy

Monoclonal antibodies (mAbs) are laboratory-produced antibodies with defined specificity. They can:

• Neutralize viruses directly (block receptor binding)
• Recruit immune cells to kill infected cells (Fc-mediated mechanisms)
• Block cytokine signaling to modulate inflammatory responses

For antiviral use:

• Nirsevimab (Beyfortus): RSV-neutralizing mAb for infants
• COVID-19 mAbs: tixagevimab/cilgavimab, bebtelovimab (now largely obsolete due to Omicron immune evasion)

For inflammatory disease associated with infection:

• Tocilizumab (IL-6R): reduced mortality in severe COVID-19 cytokine storm
• Baricitinib (JAK1/2): also effective in severe COVID-19

Cancer Immunotherapy: Applying Immune Principles

The same principles that make vaccines and antivirals work also underlie cancer immunotherapy:

Checkpoint inhibitors (covered in the adaptive immunity chapter) release T cell inhibition in tumors.

CAR-T cell therapy: T cells are extracted from a patient, genetically engineered to express a chimeric antigen receptor (CAR) targeting a tumor antigen (CD19 in B-cell cancers, BCMA in multiple myeloma), expanded, and infused back. The CAR combines an antibody's antigen recognition (no MHC restriction required) with T cell signaling domains. Approved CAR-T products achieve complete remissions in >40% of relapsed/refractory B cell lymphoma.

Cancer vaccines: Using tumor-specific neoantigens (from sequencing the tumor) to vaccinate a patient against their own cancer. mRNA-based personalized neoantigen vaccines are in Phase 2/3 trials for melanoma and other cancers.

Bispecific antibodies: Antibodies engineered to bind both a T cell surface protein (CD3) and a tumor antigen, physically forcing a T cell to contact and kill the tumor cell. Blinatumomab (CD19xCD3) and tebentafusp are approved examples.

Computational Roles in Vaccine and Therapy Development

Bioinformatics contributes at every stage:

• Antigen selection: Identifying conserved, immunogenic viral proteins from sequence analysis
• Variant surveillance: Monitoring for escape mutations in vaccine target regions (spike protein evolution monitoring was central to COVID response)
• HLA-epitope prediction: Predicting which peptides from a pathogen are likely to be presented and immunogenic — critical for subunit vaccine design
• Resistance surveillance: Tracking resistance mutations in HIV, HCV, influenza populations
• Clinical trial analysis: Analyzing vaccine immunogenicity from antibody titer, T cell response, and serology data
• Neoantigen-based therapy: The full computational pipeline from tumor WES to personalized vaccine

The convergence of genomics, immunology, and computation has fundamentally changed both vaccine development timelines (mRNA vaccines designed in days) and cancer treatment (personalized immunotherapy based on individual tumor mutations). This is where the skills you're building in this curriculum become directly clinically impactful.