Vaccination

Vaccination is a very effective measure for providing immunity to many infectious diseases. The discovery of vaccines played a central part in the eradication of smallpox and helped significantly reduce the incidence of potentially severe diseases such as poliomyelitis and measles. Live vaccines (attenuated, i.e. noninfective pathogens), inactivated vaccines (subunits or complete pathogens), viral vector vaccines, and nucleic acid vaccines (DNA, RNA, mRNA, or viral replicons) are used to achieve active immunization, which enables the host's immune system to build up a sustained immune response to specific pathogens. The immune response may be measured and quantified by assessing the antibody titer. In the event of potential disease (e.g., after exposure to high-risk pathogens), if the immune system is unable to produce sufficient antibodies fast enough, passive immunization can offer immediate short-term protection via direct injection of pooled antibodies for many conditions. Modern vaccines are usually well-tolerated, and adverse events are rare. However, the intervals between vaccine administration and possible contraindications must be considered.

For ACIP vaccination recommendations, see “Immunization schedule.”

• Vaccine
  • A product (e.g., dead or weakened organism) that provides immunity from a disease
  • May be administered through injection, orally, or nasally
• Vaccination: administration of a vaccine that induces an active immune reaction in form of cellular and/or humoral response, providing immunity against a pathogen
• Immunization
  • The process by which a person becomes protected from a disease
  • Vaccines and recovering from some infections cause immunization.

References:^[1]

• Herd immunity
  • Once a certain percentage of the population has received immunization, non-vaccinated individuals (e.g., children too young to receive vaccination) will also be protected.
  • Mass vaccination: Vaccination of a large number of people in the shortest possible time after the outbreak of an epidemic, with the goal of herd immunity.
• Eradication of disease
  • High immunization rates over prolonged periods of time can achieve eradication of certain diseases. ^[2]
  • To date, only two diseases have been eradicated by human efforts: smallpox (1980) and rinderpest (2011).
• Lower incidence and associated risks: The Haemophilus influenzae type b (Hib) vaccine has decreased the number of cases of invasive Hib disease (e.g., pneumonia, bacteremia, meningitis, epiglottitis, infectious arthritis) in children younger than 5 by more than 99%. ^[3]

• Mechanism of action
  • Injection of preformed antibodies induces a rapid humoral response against a specific pathogen
  • Provides only temporary protection, as antibodies have a half-life of ∼ 3 weeks and their titers decrease over time.
• Examples
  • Antitoxins
  • Humanized monoclonal antibodies
  • Maternal immunoglobulins that are transmitted via breast milk (IgA) or cross the placenta (IgG) to provide passive immunity
• Indications
  • Acute, post-exposure elimination of a pathogen
    • Viruses: rubella, rabies, hepatitis B
    • Toxins: tetanus, botulinum, diphtheria
  • Rhesus incompatibility prevention
• Application: Vaccines are available for intramuscular as well as for intravenous injection .
• Combination
  • Simultaneous vaccination
    • Two different passive vaccines may be administered simultaneously.
    • An inactivated active and a passive vaccine may be administered simultaneously (e.g., in acute hepatitis A, hepatitis B, rabies, or tetanus infection). ^[4]
  • After transfusion of certain blood products and/or immunoglobulin therapy, live vaccines should be delayed depending on the estimated amount of IgG in the transfusion. ^[5][6]

“Passive immunization Helps Beat The Disease Rapidly:” HBV, Botulinum, Tetanus, Diphtheria, and Rabies are indications for passive immunization.

• General information
  • In active immunity, the body's immune system reacts to the presence of antigens by producing antibodies.
  • In general, a combination of different active vaccinations is possible.
  • Slow onset, but immunity usually lasts for years or even a lifetime.
  • Besides vaccines and toxoids, natural infections lead to active immunization as well.
• Classification
  • Live attenuated vaccines
  • Inactivated vaccines
    • Whole vaccines
    • Subunit vaccines
      • Protein-based (subunit and toxoid vaccines)
      • Polysaccharide-based
  • Viral vector vaccines
  • Nucleic acid vaccines (DNA, RNA, mRNA, or viral replicons)

Current vaccination recommendations for the US can be found in the “Immunization schedule.”

• Definition: Modified functioning virus or bacterium that can replicate in the patient's body but does not cause disease.
• Mechanism of action
  • Similar to an infection with a “wild” pathogen and induces a cellular and humoral immune response.
  • Specific B-cells against an antigen are formed; , which induces a potent, lifelong immune response
• Administration
  • Oral vaccine or subcutaneous/intramuscular injection in children > 12 months
  • Not indicated in children < 9 months; (the rotavirus vaccine is an exception, which is first given at 6 weeks of age)
  • Second dose usually recommended to “catch” non-responders (not as a boost)
  • Multiple live vaccines can be given simultaneously, but if given at different times they should be at least 4 weeks apart to avoid possible interference.
  • May be administered simultaneously with inactivated vaccines
• Available vaccines
  • MMR: prevents measles, mumps and rubella infections
  • Varicella: against varicella-zoster virus (VZV)
  • Zoster: prevents reactivation of latent VZV (i.e., shingles)
  • Yellow fever
  • Rotavirus
  • Influenza (intranasal)
  • Smallpox
  • Adenovirus
  • Oral polio, Sabin (no longer available in the US)
  • BCG
  • Typhoid (oral, Ty21a)
• Special considerations
  • Very rarely, live attenuated vaccines may become virulent again and are thus often contraindicated in immunodeficient individuals and pregnant women .
  • HIV-positive individuals can be vaccinated with live attenuated vaccines (e.g., MMR and varicella) if their CD4 cell count is ≥ 200 cells/mm³.
  • Adenovirus vaccine is given in its nonattenuated form to military recruits.

“TYler And Paul Burnt their INFamous ROasted YELLOW-RUBy CHICKEN MEAt Very MUch”: TYphoid, Adenovirus, Polio, BCG, INFluenza, ROtavirus, YELLOW fever, RUBella, CHICKENpox, MEAsles, Varicella, and MUmps are live attenuated vaccines.

References:^[7][8]

“Beware of Hepatitis A on your TRIP:” Hepatitis A, Typhoid fever, Rabies, Influenza, and Poliomyelitis.

References:^[9][10]

• Definition: an unrelated virus (e.g., adenovirus, vesicular stomatitis virus, influenza virus) is modified to be used as a nonpathogenic vector that delivers genetic code to cells containing instructions for the production of the desired antigen. ^[11]
• Mechanism of action
  • There are two types of viral vector vaccines: replicating and nonreplicating
    • Nonreplicating vector vaccines: enter the cells and induce the production of vaccine antigens, but cannot produce new viral particles
    • Replicating vector vaccines
      • Enter the cells, inducing the production of new viral particles
      • New viral particles go on to infect other host cells, leading to the production of further viral and vaccine antigens
  • Induce both humoral and cellular immune responses
• Administration: usually injected intramuscularly, but can also be administered intranasally, intradermally, and orally
• Available vaccines
  • Ebola virus vaccine (rVSV-ZEBOV; Ervebo)
  • COVID-19 vaccine (Janssen COVID-19 vaccine, Vaxzevria, Sputnik V vaccine)
• Special considerations
  • Preexisting immunity to the virus that serves as the vector may affect the effectiveness of a vaccine. ^[12]
  • Less strict storage and handling conditions than nucleic acid vaccines
  • Viral vectors are genetically stable and lack a viral genome and nonstructural proteins. Therefore, they do not interact or integrate into the host's DNA and are nonpathogenic.

RNA vaccines ^[13][14]

• Definition: a vaccine based on mRNA that delivers genetic code containing instructions for the production of the desired antigen to cells
• Mechanism of action
  • Two types of mRNA vaccines: nonreplicating and self-amplifying
    • Nonreplicating mRNA vaccines: contain the sequence of the desired antigen and the 5′ and 3′ untranslated regions
    • Self-amplifying mRNA vaccines: contain the sequence of the desired antigen and the viral replication machinery (e.g., RNA polymerase) that enables intracellular RNA amplification
  • Both types induce humoral as well as cellular immune responses.
• Administration
  • Injected intramuscularly or intradermally
  • Require multiple doses
• Available vaccines: COVID-19 vaccines (e.g., Comirnaty, Spikevax) contain modified mRNA embedded in lipid nanoparticles that encodes for the spike protein mRNA sequence of SARS-CoV-2
• Special considerations
  • mRNA is a nonintegrating platform that is degraded by normal cellular processes. Due to its transitory nature, mRNA does not interact or integrate into the DNA and bears no risk of insertional mutagenesis. (e.g., COVID-19 vaccines are safe to use during pregnancy)
  • There is no potential risk of infection as mRNA is nonpathogenic.
  • Require strict cold-chain
  • Different techniques can be used to deliver the vaccine (e.g., injection of naked mRNA or encapsulated within nanoparticles or polyplex)

DNA vaccines ^[15]

• Definition: A specific antigen-coding DNA sequence is introduced using a genetically engineered plasmid to induce endogenous antigen production in the host.
• Mechanism of action
  • After entering the cells, the vaccine antigen is expressed from the DNA construct.
  • Induce both humoral and cellular immune responses
• Administration
  • Intramuscularly or intradermally
  • Require multiple doses
• Available vaccines: No DNA vaccines have been approved for human use in the United States.
• Special considerations
  • Potential advantages observed in animal models are improved vaccine stability and the use of nonpathogenic agents.
  • In order to properly deliver the vaccine and ensure cellular uptake, injection needs to be followed by electroporation.

Common adverse effects ^[16][17][18]

• Affects ∼ 1/3
• Usually begin within the first 48–72 hours after administration and last 1–2 days
• Symptoms
  • Local swelling, redness, and pain at the injection site
  • Low-grade fever (postvaccination fever)
  • Headaches
  • Fatigue
  • Flu-like symptoms
• Live attenuated vaccine: can cause mild form of the disease, usually appearing within 1–3 weeks of administration; : usually caused by replication of the attenuated vaccine strain

Rare adverse effects ^[16][17][18]

• Cardiovascular complications: observed in young men who received mRNA vaccines (COVID-19 vaccines) ^[19]
  • Pericarditis
  • Myocarditis
  • Myocardial ischemia
• Serious allergic reaction (generally < 1 per million doses)
• Live attenuated vaccine: attenuated course of the disease following immunization (e.g., vaccine-related measles)
• Vaccine injury (∼ 1/1,000,000): permanent injury from a vaccination or a vaccine-related complication (e.g., encephalopathy, seizures, brachial neuritis)

There is no link between autism and vaccines or their ingredients. ^[20][21]

Precautions

• General precautions
  • A precaution is a condition in the recipient that might increase the risk for serious adverse reactions or interfere with a vaccine's ability to produce immunity.
  • Generally, vaccination should be deferred when a precaution is present, except when the benefits of protection outweigh the risks.
  • Acute moderate or severe illness (with or without fever)
• Special precautions
  • Rotavirus vaccine: uncorrected GI tract malformation (e.g., Meckel's diverticulum)
  • Egg protein-containing vaccines: allergic reactions other than urticaria (e.g., angioedema, bronchospasm) to egg products
  • Pertussis vaccine: progressive or unstable neurologic disorders (e.g., uncontrolled epilepsy, infantile spasms, progressive encephalopathy) ^[22]
  • Tetanus toxoid-containing vaccines
    • Development of Guillain-Barré syndrome within 6 weeks of a previous dose
    • Arthus reaction after a previous dose ^[22]

Contraindications ^[23]

• General contraindications
  • Vaccines are generally contraindicated in recipients with conditions that increase the risk for severe vaccine reactions or in whom the vaccine may exacerbate the condition.
  • Previous severe adverse reactions (e.g., anaphylaxis)
  • Severe adverse reactions to a vaccine component (e.g., egg protein in yellow fever vaccine, yeast in hepatitis B vaccine)
• Contraindications to live vaccines
  • Rotavirus vaccine
    • Severe combined immunodeficiency (SCID)
    • History of intussusception ^[24]
  • Pertussis vaccines: risk of encephalopathy (e.g., prolonged seizures, decreased level of consciousness, coma) within 7 days following a previous dose
  • Live, attenuated virus vaccinations ^[22]
    • Pregnant individuals
    • Immunodeficient individuals (e.g., individuals receiving chemotherapy or long-term immunosuppressive therapy, individuals with congenital immunodeficiencies, patients with HIV and severe immunocompromise)
    • Individuals receiving IVIG therapy (e.g., for Kawasaki disease)
• False contraindications ^[25][26]
  • Fever within 48 hours
  • Current or recent mild illness (e.g., rhinorrhea, otitis media, mild diarrhea)
  • Current or recent antibiotic therapy (exception is oral live typhoid vaccine )
  • Current or recent low-dose and/or short-term steroid use (i.e., < 2 mg/kg/day or < 20 mg/day, < 14 days)
  • Previous mild or moderate localized cutaneous reaction (e.g., swelling, redness, soreness) following any vaccination
  • Preterm infants
    • Should be immunized according to chronological age, not gestational age
    • The exception is the hepatitis B vaccine: vaccination should be delayed by a month or until hospital discharge for infants weighing < 2 kg born to HBsAg-negative mothers.
    • Adjustment according to weight: no dose adjustment is needed

All children should be immunized with the standard doses of vaccines according to their chronological age; doses should not be adjusted to weight or height.

Immunizations during pregnancy, vaccinations in preterm infants, and vaccinations in individuals with HIV are detailed in the “Immunization schedule” article.

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