Vaccines and Neurologic Disease

James J. Sejvar, M.D.

Semin Neurol. 2011;31(3):338-355.

Abstract and Introduction

Abstract

Vaccines have undoubtedly been a medical milestone, preventing immeasurable morbidity and mortality from infectious diseases worldwide. Modern vaccines have tremendously reduced the global impact of numerous infections; they have succeeded in eliminating smallpox completely. However, the nature by which vaccines confer their protection—by stimulation of the immune system—means that in rare cases, adverse often immunologically mediated events may occur following vaccination. Some of the most severe of these involve the nervous system. The author provides an overview of the mechanisms of vaccinology, and describes the various vaccines available for particular neurologic illnesses. Possible neurologic adverse events following vaccinations, and the possible mechanisms of these events, are also discussed. Finally, procedures in place to ensure vaccine safety are reviewed.

Introduction

Among the medical milestones of human history, the discovery and implementation of vaccination has undoubtedly ranked among the top. The development of vaccines against various infectious diseases has ameliorated morbidity and mortality worldwide.^[1] Despite its relatively recent development, vaccination has successfully controlled at least 12 major diseases in most of the world, and has successfully eradicated one, smallpox, from the globe.^[2] The nature by which vaccines work, however—by stimulation of the innate immune system—carries with it the risk of rare adverse events associated with vaccination. Here I will explore the various neurologic infections that have been controlled by vaccines as well as the occurrence of rare neurologic adverse events associated with vaccination.

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Abstract and Introduction
Vaccines and Vaccine Immunology
Vaccines and Specific Neurologic Adverse Events
Conclusions
References

Table 1. Vaccines Against Viral, Bacterial, and Toxin Agents of Neurologic Disease
Disease	Organism/Agent	Neurologic Syndrome(s)	Vaccine Type(s)	Representative Vaccine Formulation(s)**	Indications
Viral Diseases
Influenza	Single-stranded RNA Orthomyxovirus	Influenza-associated encephalopathy (rare)	Inactivated (trivalent inactivated vaccine, TIV)	TIV, LAIV—various manufacturers; includes most commonly circulating influenza viruses; reformulated seasonally	TIV, LAIV*: All persons >6 months of age should be vaccinated; when vaccine supply is limited, then high-risk groups should be targeted^†
Influenza	Single-stranded RNA Orthomyxovirus	Influenza-associated encephalopathy (rare)	Live-attenuated influenza vaccine (LAIV)
Measles	Negative-stranded RNA paramyxovirus	Encephalitis, cerebellitis, aseptic meningitis; subacute sclerosing panencephalitis (SSPE) (rare)	Live-attenuated	MMR, MR, M (various manufacturers)	Routine childhood vaccination (worldwide)
Measles	Negative-stranded RNA paramyxovirus		Live-attenuated	MMR, MR, M (various manufacturers)	Immunization of persons without immunity
Mumps	Negative-stranded RNA paramyxovirus	Encephalitis, aseptic meningitis, cerebellitis	Live-attenuated	MMR, Mu (various manufacturers)	Routine childhood vaccinations (worldwide)
Mumps	Negative-stranded RNA paramyxovirus	Encephalitis, aseptic meningitis, cerebellitis	Live-attenuated	MMR, Mu (various manufacturers)	Immunization of persons without immunity
Rubella	Positive-stranded RNA Togavirus	Postinfectious encephalitis; progressive rubella panencephalitis (PRP) (rare); congenital rubella	Live-attenuated	MMR, MR, R (various manufacturers)	Routine childhood vaccination (worldwide)
					Immunization of persons without immunity
					Vaccination of seronegative pregnant women
Polio	Positive-stranded RNA picornavirus	Aseptic meningitis; anterior myelitis producing acute flaccid paralysis (AFP)	Live-attenuated oral polio vaccine (OPV)	OPV (various manufacturers)	IPV: Routine childhood vaccination in children in North America, Europe, Australia, New Zealand^¶; booster to adults traveling to polio-endemic countries
Polio	Positive-stranded RNA picornavirus		Inactivated intramuscular polio vaccine (IPV)	IPV (various manufacturers)	OPV: Routine childhood immunization of children in developing or polio-endemic countries; control of outbreaks; use in national/subnational immunization campaigns
Rabies	Negative-stranded RNA rhabdovirus	Progressive, fatal rhombencephalitis; peripheral neuritis	Inactivated, nerve-tissue derived (Semple, Fuenzalida); inactivated, purified duck embryo cell derived (PDEV); purified chick embryo cell derived (PCEV); Inactivated, human diploid cell vaccine (HDCV)	N/A	Semple, Fuenzalida: Postexposure prophylaxis, only used in Asia, Africa (Semple), and South America (Fuenzalida)
Rabies	Negative-stranded RNA rhabdovirus	Progressive, fatal rhombencephalitis; peripheral neuritis		N/A	PDEV, Inactivated Cell Culture: postexposure prophylaxis; preexposure vaccination in high-risk persons (veterinarians, hunters, animal control personnel); preexposure vaccination in travelers to rabies-endemic countries engaging in high-risk activities (eco-tourism, spelunking, etc.)
Japanese encephalitis	Positive-stranded RNA flavivirus	Aseptic meningitis, encephalitis, anterior myelitis	Inactivated, mouse-brain derived	N/A	Vaccination for children in endemic areas
			Inactivated, PHKC-derived		Vaccination for other susceptible persons in endemic areas
			Live-attenuated, PHKC-derived		Vaccination for travelers to endemic areas with significant risk of exposure
Tick-borne encephalitis	Positive-stranded RNA flavivirus	Aseptic meningitis, encephalitis, anterior myelitis	Inactivated, PCEC-derived	FSME-Immun®^‖ (Baxter, Zurich, Switzerland^‖; Mississauga, Ontario, Canada)	Vaccination for children, at-risk persons in endemic areas^#
Tick-borne encephalitis	Positive-stranded RNA flavivirus	Aseptic meningitis, encephalitis, anterior myelitis	Inactivated, PCEC-derived	Encepur® (Novartis, Basel, Switzerland)	Vaccination for travelers to endemic areas with significant risk exposure
Eastern/Western/Venezuelan equine encephalitis	Positive-stranded RNA togavirus (all)	Aseptic meningitis, encephalitis	Inactivated	Inactivated: VEE TC-83; EEE TSI-GSD-104; WEE TSI-GSD-210	Limited use, not available to general public
Eastern/Western/Venezuelan equine encephalitis	Positive-stranded RNA togavirus (all)	Aseptic meningitis, encephalitis	Live-attenuated (VEE only)	Live-attenuated: VEE TC-83 (live)	Vaccination of military personnel, laboratory workers
Varicella zoster	Double-stranded DNA herpesvirus	Cerebellitis, encephalitis	Live-attenuated	MMRV (Proquad^®‖, Merck & Co., Inc., Whitehouse Station, NJ), V (various manufacturers)	Routine childhood vaccination in North America, Europe, Australia, New Zealand
Varicella zoster	Double-stranded DNA herpesvirus	Cerebellitis, encephalitis	Live-attenuated		Immunization of targeted populations (healthcare workers, immunosuppressed)
Herpes zoster	Double-stranded DNA herpesvirus	Latent infection with VZV, resulting in ganglionitis with painful erythematous eruption; post-herpetic neuralgia (PHN)	Live-attenuated	Zostavax^®‖ (Merck)	Recommended for persons age 60 and over (U.S.)
Bacterial Diseases
Meningococcus	Neisseria meningitidis; gram-negative endotoxin-producing diplococcus	Bacterial meningitis, sepsis	Polysaccharide vaccines	Polysaccharide vaccines: Bivalent (serogroups A, C), trivalent (A, C, W135), quadrivalent (A, C, Y, W135)	U.S., Europe: Recommended for children at 11–12 years of age or at high-school entry
			Conjugate vaccines	Conjugate vaccines: Monovalent (serogroup C), quadrivalent (A, C, Y, W135)	Recommended for groups at risk for meningococcal meningitis (college freshmen in dormitories, prisoners, military personnel, laboratory workers)
				Control of meningococcal outbreaks
Pneumococcus	Streptococcus pneumoniae; anaerobic gram-positive diplococcus	Bacterial meningitis, sepsis	Polysaccharide vaccines	Polysaccharide vaccine: various formulations; most commonly used is 23-valent formulation	Polysaccharide vaccines: Recommended for persons >65 years, and for persons 2–64 years with conditions associated with increased risk of pneumococcal disease (immunocompromised, chronic diseases, asplenia)
			Conjugate vaccines	Conjugate vaccines: Various formulations; most commonly used is 7-valent formulation	Conjugate vaccines: Variable by country, but increasingly being incorporated into routine childhood immunization schedule worldwide
			Common protein vaccines (in development)
Toxoid Vaccines
Tetanus	Tetanospasmin, a 150kD polypeptide toxin produced by Clostridium tetani, a gram-positive, spore-forming bacillus	Localized or, more commonly, generalized spasms, hyperreflexia, trismus, autonomic instability	Inactivated toxoid	Td^‡, DT^§, DTP, DTaP (various manufacturers)	Routine primary childhood vaccination in children 6 weeks-< 7 years in most of the world
					Booster doses every 10 years generally recommended
					Postexposure wound prophylaxis in certain situations
Diphtheria	Diphtheria toxin, a 58kD polypeptide exotoxin secreted by Corynebacterium diphtheriae, a gram-positive bacillus	Palatal and facial paralysis; generalized peripheral neuropathy (uncommon)	Inactivated toxoid	Td, DT, DTP, DTaP (various manufacturers)	Routine primary childhood vaccination in children 6 weeks-<7 years in most of the world
Diphtheria			Inactivated toxoid	Td, DT, DTP, DTaP (various manufacturers)	Booster doses every 10 years generally recommended

MMR, measles, mumps, rubella vaccine; MR, measles, rubella vaccine; M, measles vaccine; PHKC, primary hamster kidney cell line; PCEC, primary chick embryo cell line.
*LAIV not recommended for persons under age 2 or over age 50; immunosuppressed.
^†High-risk groups: persons 6 months-4 years, >50 years of age; chronic medical conditions; immunosuppressed; pregnant women; persons living in crowded conditions; American Indian/Alaska Native; morbidly obese; health care workers; children and adolescents who receive long-term aspirin therapy; household contacts of those in high-risk groups.
^‡Td—Diphtheria and tetanus toxoids, adsorbed, for adult use.
^§DT—Diphtheria and tetanus toxoids, adsorbed, for pediatric use.
^‖Brand names used only for single-source vaccines.
^¶Specific use of IPV and OPV schedules for routine immunizations may differ from country to country in these areas.
Routine childhood vaccination not conducted in all endemic areas.
**Indications for various vaccines and vaccine formulations may vary considerably within and between countries, are subject to frequent changes based upon newly available evidence and epidemiologic circumstances, and may vary in terms of composition of composite vaccines. The Formulations and Indications provided in this table are intended as an overview, and are subject to frequent changes.

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