Clinical aspects

Description

	• Traditional vaccines use either a related immunogen for cross-reactive immunity or attenuated organisms.
	• mRNA vaccines instruct body cells to make copies of pathogenic proteins of an infective organism so the body can produce antigens without actually using the infective organism.
	• Genetically engineered vectors are used for delivering nucleic acid vaccines.
	• An adjuvant, usually an aluminium salt, is used to increase the immune response to an antigen.
	• Vaccines are also in development for treatment of neurologic disorders, eg, neurodegenerative disorders, glioblastoma, etc.
	• Vaccines are generally safe, but injection site reactions, allergic reactions, and anaphylaxis are not unusual. Neurologic sequelae are rare.

Three well-known approaches for vaccine construction are:

	(1) The use of a related immunogen to achieve cross-reactive immunity against the more pathogenic organism (eg, the use of cowpox for smallpox immunization).
	(2) The use of attenuated or weaker version of an organism by passage of an organism in culture or animals with selection of a weaker version (eg, the Bacille Calmette-Guerin vaccine).
	(3) mRNA vaccines, eg, for protection against COViD-19, instruct our body cells to make harmless copies of “spike protein,” which is found on the surface of the SARS-CoV-2 virus. After the protein piece is made, the cell breaks down the instructions and removes them. Our immune system recognizes the protein as foreign and makes antibodies against COVID-19 as would happen in natural infection. There is no risk of transmission of infection as no live virus is used.

Bacterial vaccines were broadly of 3 types: (1) killed suspensions prepared from virulent organisms, (2) live preparations of strains selected for attenuation by manipulation of culture conditions, (3) and toxoids prepared by detoxification of crude bacterial toxins. Viral vaccines corresponded to the first 2 types of bacterial vaccines.

Newer developments include the use of peptide vaccines based on purified components of the pathogens and polysaccharide-protein conjugates. Many of the developments in vaccination technology are based on tools of molecular biology and involve genetic engineering as shown in Table 1.

Table 1. Genetically Engineered Vaccines

Approach	Basis	Example
Genetic engineering of an organism	Deletion or mutation of a gene encoding virulence of the organism.	Simian immunodeficiency virus vaccine using deletion of Nef gene
Vaccinia viral vector	Gene transfer to deliver the antigen-encoding gene to the host.	HIV-1 vaccine for AIDS
Alpha virus vector	Alpha viruses are RNA viruses, and replicons are engineered to replace the gene with by a sequence encoding the antigen.	Venezuelan equine encephalitis
Bacterial vectors	Bacteria are engineered to serve as vectors for delivering plasmid DNA into cells that the bacterium invades.	Attenuated vector versions of Listeria monocytogenes for lymphocytic choriomeningitis vaccine
Nucleic acid vaccines: DNA and RNA vaccines	Bacterial plasmids carrying genes encoding pathogen or tumor antigens.	Several infectious diseases Cancer vaccines
Dendritic cell vaccines	Human dendritic cells pulsed with RNA-encoded tumor antigen	Cancer vaccines

DNA vaccines. In a DNA vaccine, the antigen of interest is cloned into the bacterial plasmid that is engineered to augment the expression of inserted gene in the mammalian cells. After injection into a living animal, the plasmid enters the host cell and directs the synthesis of the antigen it encodes. In a naked DNA vaccine, the DNA has been freed of all the proteins in the usual DNA-protein complex. Naked DNA vaccines derived from plasmids could bypass the numerous problems associated with other vectors, such as immune response against the delivery vector. This has several advantages over immunization with exogenous recombinant proteins or microorganisms:

	• Elimination of the threat of introducing a potentially virulent virus associated with “attenuated” vaccines.
	• DNA can be stored in a dry, powdered form for years and still retain its activity.
	• Low doses of a proper gene construct can induce protective immunization.
	• A single application can lead to long-lasting immunity, eliminate the need for booster doses, and increase compliance.

Messenger RNA (mRNA) vaccines. mRNA vaccines have the following advantages:

	• Technology allows fast production in response to a pandemic scenario.
	• These may become a novel, widely applicable and easy-to-handle prophylactic class of vaccines against infectious diseases.
	• mRNA vaccines overcome the drawbacks of many other prophylactic vaccination methods, including DNA-based approaches that can have insufficient clinical efficacy or safety and may cause residual vector immunogenicity.
	• Production of RNActive vaccines is highly flexible; these can be rapidly supplied for a variety of virus strains and subtypes identified in response to pandemic scenarios.
	• mRNA vaccines have been shown to induce balanced, long-lived, and protective immunity against COVID-19.

Delivery systems and adjuvants for vaccines. An adjuvant, usually an aluminium salt, is used to increase the immune response to an antigen. Cytokines are now being evaluated as adjuvants for vaccines. Traditionally, most vaccinations have been administered by injection. An oral route of delivery was first used for the polio vaccine. Other methods of delivery for vaccines are transmucosal, such as the intranasal and transdermal route shown by a gene gun in the case of DNA vaccines.

Vaccination is used for both prophylaxis and treatment of neurologic disorders, which includes mainly infections but also other diseases (eg, malignant brain tumors and multiple sclerosis).

Indications

Neurologic disorders where vaccines have either been used or are in development are shown in Table 2.

Table 2. Disorders Affecting the Nervous System for Which Vaccines Are in Development or Have Been Used

Prevention of infections to the central nervous system:
	• Viral encephalitis
		- Eastern equine encephalitis - Japanese encephalitis - Tick-borne encephalitis - Venezuelan equine encephalitis - Western equine encephalitis
	• Lyme disease
	• Meningitis
		- Meningococcal meningitis - Lymphocytic choriomeningitis - Haemophilus influenzae
	• Poliomyelitis • Rabies • Tetanus • Herpes zoster infections
Prevention of congenital and neonatal infection:
	• Congenital rubella • Congenital cytomegalovirus • Congenital HIV-1 infections • Neonatal meningitis
Prevention of infections that can affect the nervous system:
	- COVID-19 - HIV-1 - Herpes simplex - Leprosy - Malaria - Tuberculosis
Treatment of degenerative neurologic disorders:
	• Alzheimer disease • Amyotrophic lateral sclerosis
Treatment of demyelinating neurologic disorders
	• Multiple sclerosis
Treatment of addiction
	• Cocaine addiction • Nicotine addiction • Opioid addiction • Methamphetamine addiction
Therapeutic vaccines for primary malignancies of the nervous system
	• Glioblastoma
Vaccines for neuroprotection in CNS trauma
	• Spinal cord injury • Traumatic brain injury

Contraindications

Prophylactic vaccination should be postponed in patients suffering from acute infections. Live vaccines should not be given to patients on immunosuppressant therapy or systemic corticosteroids.

Results

Lyme disease vaccine. A Lyme disease vaccine that consists of recombinant Borrelia burgdorferi outer surface lipoprotein A was approved by the Food and Drug Administration in 1998 and was shown to be effective in preventing Lyme disease after exposure. The only approved vaccine was subsequently voluntarily withdrawn from the market by the manufacturer due to a combination of factors that included concerns raised by anti-vaccine groups regarding vaccine safety, vaccine cost, uncertainty regarding risk of disease, and lack of sales (38).

Herpes zoster vaccine. In 2006, the FDA approved the first herpes zoster vaccine, Zostavax, which is intended to reduce the risk of herpes zoster in persons 60 years of age and older. Zostavax markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults in a randomized controlled trial (31). A clinical trial showed that herpes zoster and zoster vaccine generated comparable varicella-zoster virus-specific humoral and cell-mediated immunity (57). Higher varicella-zoster virus and cell-mediated immunity at herpes zoster onset was associated with reduced severity of herpes zoster and less postherpetic neuralgia. A study of serious adverse events in a randomized, placebo-controlled trial of herpes zoster vaccine showed that it was well tolerated in older, immunocompetent adults, and rates of hospitalization or death did not differ between vaccine and placebo recipients (48). The results of a study that examined a large cohort of adults who received the zoster vaccine for an increased risk of pre-specified adverse events showed that the zoster vaccine is safe and well-tolerated, with a small increased risk of allergic reactions within 1 to 7 days after vaccination (52). The 3-year Shingles Prevention Study showed that Zostavax significantly reduced burden of disease due to herpes zoster and postherpetic neuralgia and led to the recommendation of its use for immunization of immunocompetent individuals over age 60 years with no history of recent zoster (13). In a large study of older individuals, zoster vaccination was associated with reduction in incident zoster, including among those with immunosuppression (23).

ZOE-50, a randomized, phase 3, placebo-controlled study of herpes zoster adjuvanted subunit vaccine (HZ/su, Shingrix) was conducted in countries in Europe, North America, Latin America, and Asia-Australia. HZ/su vaccine significantly reduced the risk of herpes zoster among adults who were 50 years of age or older, and overall efficacy was well preserved among participants who were 70 years of age or older (21). In 2 further clinical trials of HZ/su vaccine, ZOE-70, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older with comparable efficacy to ZOE-50 (07).

In ZOE-70, Shingrix was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older with comparable efficacy to ZOE-50. In a pooled analysis of many studies, the vaccine demonstrated efficacy against herpes zoster of over 90% in adults aged 50 and older and in those aged 70 and older. Efficacy was sustained during the 4-year follow-up period. Shingrix was approved by the FDA in 2017. In 2018, drug regulators in Europe and Japan approved Shingrix to prevent herpes zoster and postherpetic neuralgia.

Cytomegalovirus vaccine. How cytomegalovirus stimulates the immune system is not known. It is a complex virus that encodes for hundreds of proteins, and the portions of the virus that are needed to make a protective immune response have not been determined adequately. A phase 2, placebo-controlled, randomized, double-blind trial has shown that a vaccine consisting of recombinant cytomegalovirus envelope glycoprotein B has the potential to decrease incident cases of maternal and congenital infection with cytomegalovirus, which can cause hearing, cognitive, and motor impairments in newborns (32).

Meningococcal meningitis vaccines. Commonly available vaccines contain purified polysaccharide from Neisseria meningitidis groups A and C or groups A, C, Y, and W135. The United Kingdom's Medicine Control Agency has approved a conjugate vaccine against disease caused by the bacterium. It was initially used in the United Kingdom for vaccinating children 12 months of age and older, adolescents, and adults. Market approval in the United Kingdom was also granted to a group C meningococcal conjugate vaccine, MenC, which provides a longer and stronger immune response across a wider age range than nonconjugate vaccines. MenC has proved to be highly safe and effective, but there is some uncertainty about the duration of effectiveness of this vaccine, even though it is extended by booster doses.

Two meningococcal group B vaccines based on meningococcal outer-membrane proteins as the primary antigens have been licensed in the United States: CMenB and MenB-FHbp.

4CMenB (Bexsero). 4CMenB is a 4-component combination comprised of 1 variant of the factor H-binding protein (FHbp), Neisseria adhesin A, neisserial heparin-binding antigen, and outer-membrane vesicles containing the porin proteinA (PorA). It is also approved by the European Commission for use in individuals greater than or equal to 2 months of age. A theoretical transmission model in the United Kingdom showed that routine vaccination at ages 2, 3, 4, 12 months, and 14 years combined with a 5-year catch-up program in toddlers aged 12 to 24 months and adolescents aged 15 to 18 years would lead to a 94% reduction in meningococcal cases (14). Three doses of 4CMenB provide approximately 60% protection against invasive meningococcal group B disease in infants (20). 4CMenB does not provide herd protection against encapsulated meningococci, and it will protect only persons who are adequately immunized (27).

MenB-FHbp (Trumenba). Trumenba (bivalent rLP2086) includes 2 lipidated variants of FHbp. It was approved by the FDA in 2014 for immunization against invasive meningococcal disease resulting from meningococcal serogroup B. It was approved in Europe in 2017 for active immunization of individuals 10 years and older. Trumenba is formulated as an injectable suspension. Its active substances are 2 recombinant lipidated factor H binding protein (fHbp) variants from subfamilies A and B, which are located on the surface of Neisseria meningitidis serogroup B. Trumenba induces protective serum bactericidal antibody responses to several meningococcal serogroup B test strains that express fHbp variants that cause invasive disease.

Research for new vaccines. The completion of the genome sequence of N meningitidis represents a major step forward in the molecular understanding of an important human pathogen, and this information is now being used in the search for new vaccine candidates. Using information derived from the DNA sequence, investigators were able to identify novel surface proteins in N meningitidis. These newly discovered proteins behave differently from those previously identified and are present across a wide range of strains. These proteins can stimulate an antibody response capable of killing the bacterium. This property is known to correlate with vaccine efficacy in humans. Work is now underway to identify the most promising vaccine candidates while incorporating 1 or more of these surface-expressed proteins. This genomics-based approach enables the creation of a vaccine capable of protecting against the broad diversity of invasive strains of this virulent microorganism.

Gene expression profiling by using microarrays gives a better understanding of what happens when bacteria interact with the host cells. Microarray technology is considered a valid approach for identifying new vaccine candidates and complements other genome mining strategies used for vaccine discovery.

Japanese encephalitis vaccines. The attenuated Japanese encephalitis virus live vaccine SA14-14-2 is prepared from wild-type strain SA14. It has been in use for many years and is effective in preventing this disease in children without any serious adverse effects. A single dose of the vaccine is highly efficacious in preventing Japanese encephalitis when administered only days or weeks before exposure to infection. A study of the 5-year Japanese encephalitis immunization program using SA14-14-2 Japanese encephalitis vaccine implemented in Nepal during 2006 through 2011 showed that cases of the disease were reduced by 78% (53).

Ixiaro (Intercell AG), an inactivated vaccine, has been shown to be safe and effective in clinical trials for preventing Japanese encephalitis (19). Ixiaro is manufactured using tissue culture rather than live organisms and is approved in the United States, Canada, Europe, and Australia.

IMOJEV(R), a recombinant chimeric virus vaccine, was developed by replacing the cDNA encoding the envelope proteins of the yellow fever virus vaccine vector with that of an attenuated Japanese encephalitis virus strain and was found to be safe, highly immunogenic, and capable of inducing long-lasting immunity in both preclinical studies and phase 3 clinical trials (01). It was approved in Thailand and Australia.

Tick-borne encephalitis vaccine. Immunization with the whole-killed virus vaccine is shown to protect mice against a subsequent challenge with a highly lethal dose of tick-borne encephalitis virus. This protection is mediated by antibodies to the surface protein of tick-borne encephalitis virus, glycoprotein E. Although this vaccine is highly effective, protection has been shown to be nonequivalent with complete neutralization of the challenge virus. An inactivated and parenteral vaccine is commercially available for immunization against tick-borne encephalitis.

Experimental studies on higher primates have shown that RepliVax for tick-borne encephalitis based on a West Nile virus backbone induces significantly more durable humoral immune response after a single dose compared with 3 doses of a licensed, adjuvanted human inactivated vaccine (42).

Vaccine for West Nile virus infection. This virus targets neurons to cause lethal encephalitis, primarily in elderly and immunocompromised patients. Although several vaccines for West Nile virus have been developed for animals, none are available for humans. Intravenous immunoglobulin and pooled human West Nile virus convalescent sera (WNV-IVIG) were shown to inhibit development of lethal West Nile virus encephalitis in mice by suppressing CNS inflammation (50).

Vaccine for Zika virus. Zika virus is a mosquito-borne flavivirus closely related to dengue virus. There is evidence now that Zika virus is less benign than initially thought. Hundreds of cases of Guillain-Barré syndrome have sprung up in the wake of Zika infection, but it is an explosion of microcephaly among infants born to infected women that has caused Brazil to declare Zika a public health emergency. The development of a safe and effective Zika virus vaccine is an important component of a long-term solution. Prevention of congenital anomalies through vaccination of women during pregnancy faces several challenges (28). To protect the developing fetus, one must achieve protective immunity before the time of peak vulnerability, which is probably during the first and early second trimesters.

Rotavirus vaccine. Rotavirus is a common cause of acute gastroenteritis and can also cause generalized tonic-clonic afebrile seizures due to involvement of the brain. The rotavirus vaccine has been effective in decreasing hospitalizations due to acute gastroenteritis. A study has provided evidence for a decrease in seizure hospitalizations following the introduction of the rotavirus vaccine in the United States, with the greatest impact in children who have a high rotavirus-associated disease burden and during rotavirus infection season (39).

Vaccines against herpes simplex virus. The development of many promising herpes simplex virus vaccines has been terminated because of modest or controversial therapeutic effects in humans. Several promising vaccine candidates have shown efficacy in animal models, but these need to be tested in humans for adequate therapeutic efficacy to justify further development (58).

Vaccines against COVID-19. Because of neuro-COVID and lack of specific antiviral agents, prophylactic vaccines are the most important measure for control. As of April 2, 2021, 3 vaccines have emergency use authorization from the United States Food and Drug Administration; a 4th is under consideration having already won approval in the European Union and United Kingdom. COVID-19 vaccines provide better and more durable immunity that natural recovery from the disease. Every individual in a community or a country does not need to be vaccinated; the aim is to achieve “herd immunity,” which is likely to occur if the number of those vaccinated plus those who have developed natural immunity to COVID-19 after a nonsymptomatic infection or recovery from infection, exceeds 70% of the population.

BNT162b2 (BioNTech and Pfizer). This vaccine combines mRNA format and target antigen. BNT162b2 encodes an optimized SARS-CoV-2 full-length spike protein antigen. It showed 95% efficacy in phase 3 clinical trials for prevention of COVID-19 and received emergency use authorization from the US Food and Drug Administration in December 2020. The vaccine is given in 2 doses 3 weeks apart. The efficacy of this vaccine is still 93% after 6 months. A nationwide study of mass vaccination suggests the BNT162b2 mRNA vaccine is effective for a wide range of COVID-19-related outcomes, which is consistent with the findings of the phase 3 randomized trial (08).

mRNA-1273 (Moderna and Lonza). In a phase 1 study on healthy volunteers, the mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified (16). The investigators also tested the antibodies taken from study participants against actual samples of SARS-CoV-2 and found their ability to neutralize virus was at least equivalent to that found in persons who had recovered from infection. In a phase 3 trial on 30,000 persons, the efficacy of the vaccine was 94.1% (02). It received emergency use authorization from the US Food and Drug Administration in December 2020. The vaccine is given in 2 doses 4 weeks apart.

Adenovirus-based vaccine (Johnson & Johnson). This is an adenovirus-based vaccine where the viral DNA is modified to produce a key part of the SARS-CoV-2 virus particle to which the body then develops an immune response. The adenovirus that delivers the SARS-CoV-2 DNA particle cannot multiply, so it does not cause infection. A single dose of vaccine was 66% effective in preventing moderate to severe COVID-19 and 100% effective in preventing COVID-19-related hospitalization and death. It received emergency use authorization from the US Food and Drug Administration in February 2021.

ChAdOx1 nCoV-19 (AstraZeneca/Oxford) vaccine. This vaccine targets the viral spike protein and is based on chimpanzee adenovirus vaccine vector (ChAdOx1) technology, which generates a strong single-dose immune response, and is not a replicating virus, so it cannot cause infection in the vaccinated individual. Chimpanzee adenoviral vectors are a very well-studied vaccine type, having been used safely in thousands of subjects, from 1 week to 90 years of age, in vaccines targeting over 10 different diseases. Immune responses from other coronavirus studies suggest that spike proteins are a good target for a vaccine. The Oxford vaccine contains the genetic sequence of the surface spike protein inside the ChAdOx1 construct. After vaccination, the surface spike protein of the coronavirus is produced, which primes the immune system to attack the coronavirus if it later infects the body. What this vaccine does particularly well is trigger both arms of the immune system: humoral immunity (ie, the system-wide generation of antibodies against the virus) and cellular immunity (ie, the activation of immune system T cells that attack human cells infected with the COVID-19 virus). This technique has been used previously to develop a vaccine for MERS--another human coronavirus disease. Phase III clinical trials showed an efficacy of 73%. This vaccine is approved in the UK, India, and a few other countries, but Food and Drug approval in the United States is pending.

Other vaccines. China and Russia have COVID-19 vaccines that are being used in some countries. Two additional vaccines are in development in the United States and Europe. The main concern is whether current vaccines will continue to protect against new variants of SARS-CoV-2.

Neuroprotective vaccine in neurodegenerative disorders. Immunological approaches to neuroprotection are based on the concept that T cells can play an important role without causing autoimmune disorders. This could be accomplished by vaccination with a universal weak T cell-reactive antigen. The hypothesis that T cells, which home to the damaged area in the brain, may modulate local microglial response and protect against neurodegeneration is supported by experimental studies, but there is no product in development based on it.

Vaccines for Alzheimer disease. In earlier studies, immunization with a 42 amino acid form of the amyloid-beta peptide significantly reduced preexisting amyloid plaque and inhibited further plaque formation in the brains of transgenic mouse model of Alzheimer disease. In phase 1 clinical studies, AN-1792 appeared to halt the progress of Alzheimer disease and was found to be safe and well tolerated, but development was discontinued in phase 2 in 2002 because of complication of encephalitis in patients treated with AN-1792. Release of antigenic peptides derived from beta-amyloid processing was considered to enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.

Further animal experimental work on immunization with nonamyloidogenic amyloid beta derivatives represented a potentially safer therapeutic approach toward reduction of amyloid burden in Alzheimer disease than using toxic amyloid beta fibrils. Several immunization strategies were developed for Alzheimer disease, including selective A beta epitope targeting, antibody and adjuvant modifications to generate anti-A beta antibodies that selectively target and remove specific A beta species without evoking autoimmunity.

A generation of amyloid-beta42 DNA vaccine for Alzheimer disease, based on peptide boost immunization protocol, enhances antibody production without T cell response (22). Absence of inflammatory T cell responses greatly improves the safety aspect of this vaccine as compared to AN-1792 for possible clinical use.

As of April 2, 2021, 41 clinical trials of vaccines for Alzheimer disease are listed on the ClinicalTrials.gov website. Only 4 of these is active; the rest are either not started, completed, or terminated. The following describes an active ongoing clinical trial:

• A phase II study of safety and immunogenicity of repeated doses of ABvac40 in patients with a mild cognitive impairment or Vm-Alzheimer disease. It is the first active vaccine targeting the C-terminal end of the Aβ40 peptide (NCT03461276).

Amyotrophic lateral sclerosis. An experimental vaccine, based on bacterially purified recombinant SOD1 mutant protein as an immunogen, has been tested in a mouse model of amyotrophic lateral sclerosis and reduced the SOD1 mutant protein levels (54). These results suggest that immunization strategies should be considered as potential approaches for delaying the onset as well as for treatment of familial amyotrophic lateral sclerosis caused by SOD1 mutations. However, there is no clinical trial of a vaccine for amyotrophic lateral sclerosis.

Multiple sclerosis vaccine. Immunomodulators are used for the treatment of multiple sclerosis. Vaccines for infectious diseases have been tested for immunomodulating effect in multiple sclerosis. None of them are in active clinical development currently.

Tovaxin is a personalized autologous T-cell immunotherapy using myelin-reactive lymphocytes from the peripheral blood of patients with multiple sclerosis. An open-label dose escalation study of Tovaxin in multiple sclerosis patients has shown a trend for improvements in clinical outcomes following immunization (26). Further studies are required to provide scientific basis and proof of efficacy of Tovaxin (41).

In a double-blind, placebo-controlled trial, Bacille Calmette-Guerin vaccine for tuberculosis was shown to reduce clinically isolated demyelinating syndromes in early multiple sclerosis (40).

Currently, only 1 phase 1 clinical trial is planned for pediatric multiple sclerosis to test safety and efficacy of NeuroVax, a novel therapeutic T cell-receptor peptide vaccine (NCT02200718).

Vaccines for addiction. Anti-addiction vaccines that elicit antibodies to bind to drugs in blood circulation and block their pharmacological effects on the brain have considerable potential for treating drug abuse (47).

Cocaine addiction vaccine. Vaccination has been investigated for cocaine addiction due to the lack of an effective therapeutic agent. With this strategy, cocaine is treated as an invading pathogen. Active immunization against cocaine is achieved by linking stable cocaine-like conjugates with a foreign carrier protein to activate the immune system to produce anti-cocaine antibodies. Anti-cocaine antibodies bind to cocaine, prevent it from crossing the blood-brain barrier, slow entry into the brain, and prevent psychoactive effects on the brain. In an open clinical trial, the conjugated cocaine vaccine was well tolerated and cocaine-specific antibodies persisted at least 6 months with decreased use of cocaine (29).

Vaccine against heroin addiction. It is difficult to develop a vaccine for heroin addiction because of its rapid metabolism to morphine. A dynamic vaccine that creates antibodies against heroin and its psychoactive metabolites has been shown to be continuously effective in rat models of heroin addiction by sequestration of brain-permeable constituents of heroin in the bloodstream (45). Because this vaccine does not target opioid receptors, it can be combined with conventional treatment options.

Vaccine against opioid addiction. Fentanyl is an addictive prescription opioid that is several times more potent than morphine. An effective immunotherapy has been developed for reducing the psychoactive effects of fentanyl class drugs, and a single conjugate vaccine was shown to elicit high levels of antibodies in experimental animals with cross-reactivity for a wide panel of fentanyl analogs (04).

Vaccines for smoking cessation. Several vaccines are in development for smoking cessation. Immunization with a nicotine vaccine produces drug-specific antibodies that sequester some of the nicotine in the peripheral circulation and prevent it from entering the brain (03). The complex of nicotine attached to an antibody is too large to cross the blood-brain barrier. A phase 2 clinical trial has demonstrated that CYT002-NicQb (Cytos Biotechnology) has a favorable safety profile and is generally well tolerated. It promoted and sustained long-term abstinence from smoking when high antibody levels were achieved on vaccination.

Brain tumor vaccine. DCVax, a dendritic cell-based immunotherapy, is an active immunization tailored to a specific cancer type with either purified tumor-specific antigens or tumor cell extracts derived from patients at the time of resection. DCVax-Brain has undergone phase 2 clinical trials for glioblastoma multiforme. In 2007, the Swiss Institute of Public Health approved DCVax-Brain for the treatment of glioblastoma multiforme. In the United States, follow-up of patients from clinical trials at the end of 2007 showed that 68% of DCVax-Brain-treated patients with glioblastoma multiforme were alive after 2 years, and 26% were alive for more than 4 years, indicating that this vaccine may make a significant difference in the lives of patients with glioblastoma multiforme. It is still undergoing further clinical trials. An on-going phase 1 trial is evaluating the safety and efficacy of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma multiforme (36).

The epidermal growth factor receptor variant III (EGFRvIII) is an important vaccine target because its expression is tumor specific and has a promising role in immunotherapy of glioblastoma multiforme (49). Phase 2 clinical trials in patients with newly diagnosed glioblastoma multiforme have shown that EGFRvIII-specific immune responses significantly increased time to progression and overall survival in those receiving vaccine therapy (09). Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In phase 2 trials, rindopepimut, in combination with standard adjuvant temozolomide chemotherapy, was well tolerated with EGFRvIII-specific immune responses and improvement in progression-free and overall survival (46). A pivotal, double-blind, randomized, phase 3 trial is in progress.

Numerous trials of vaccines employing various strategies against glioblastoma multiforme are being conducted from phase 1 to phase 3. Although some have shown promising results, none has come close to curing it. Various adjuvants can enhance response to immunotherapy. Choice of an appropriate target and vaccination strategy combined with an immune modulator to increase the body's ability to mount an immune response against the tumor could lead to more durable responses in patients with glioblastoma. Several clinical trials are currently being planned to test such immunomodulators (59). There is a trend for immunotherapy to be integrated into the multimodal treatment including radiotherapy and chemotherapy for patients with primary diagnosis of glioblastoma multiforme as the actions of the individual treatment modalities may fortify each other (56; 34). Future clinical trials of brain tumor vaccines may incorporate this strategy. As of March 2020, 108 clinical trials of vaccines for glioblastoma are listed on the U.S. Government web site for clinical trials, which can be accessed at the following website: https://clinicaltrials.gov/. Only 37 of these trials are still active; the rest are completed or discontinued.

Advances in the understanding of antigen presentation, antigen recognition, and T cell activation have revolved around dendritic cells that are the most potent "professional" antigen presenting cells in the body. A vaccine containing dendritic cells derived from bone marrow and pulsed with peptides derived from autologous tumors has been tested in patients with glioblastoma and was not associated with any serious adverse effects. One of the ongoing clinical trials is “Personalized Cellular Vaccine for Recurrent Glioblastoma” (PerCellVac2). This phase 2 safety and efficacy trial on patients with recurrent glioblastoma uses immunization with personalized cellular vaccines including autologous tumor cells, antigen pulsed dendritic cells, and allogeneic peripheral blood mononuclear cells (NCT02808364). There has been no update since June 2019, and results have not been posted.

Clinical trials of various vaccine therapies using autologous tumor antigens or tumor-associated/specific antigen peptide with adjuvants have been performed to treat patients with glioblastoma. Furthermore, immune checkpoint pathway-targeted therapies including antiprogrammed cell death 1 antibody in patients with glioblastoma have started. Preclinical studies indicate that combination therapy with vaccine and immune checkpoint inhibitors may be a promising strategy for treatment of patients with glioblastoma (15).

Central nervous system trauma. Current evidence suggests that the injured central nervous system can benefit from autoimmune manipulations. Regulation of the immune system is required for the adequate phagocytic activity and growth factor activity. Boosting of this autoimmune response by vaccination is a potential strategy for neuroprotection.

Regeneration of neurons and axons following injury to the CNS is hindered by the presence of myelin and oligodendrocyte-related inhibitors of neurite outgrowth. Vaccine-based approaches have been investigated to address this issue and promote axonal regeneration and repair following traumatic CNS injury. However, there is no clinical trial listed of a vaccine for CNS trauma.

Adverse effects

Administration of a vaccine by injection may be followed by local reaction, possibly with inflammation and lymphangitis. Fever, headache, and malaise may occur a few hours following vaccination and last for 1 day to 2 days. Hypersensitivity reactions may occur, and anaphylaxis has rarely been reported. Further details of adverse effects of vaccines are listed in the product inserts of various preparations.

Neurologic adverse effects of vaccines used for infections affecting the nervous system are sometimes difficult to distinguish from the manifestations of the disease. The most significant neurologic complication of vaccination is acute disseminated encephalomyelitis, a syndrome characterized by rapid development of multifocal neurologic dysfunction. Neurologic sequelae of smallpox vaccination in the 1920s led to an awareness that such complications can follow other vaccines. Acute disseminated encephalomyelitis has been reported in association with several vaccines. These include the rabies vaccine and the Japanese encephalitis vaccine.

Meningococcal vaccine. The most commonly reported adverse event following vaccination with Trumenba (bivalent rLP2086) was injection site pain (12). Other adverse effects such as fatigue, myalgia, fever, and chills were similar as those reported in clinical trials.

Rabies vaccine. The incidence of encephalitis with original Pasteur vaccine, prepared in rabbit brain, was estimated to be from 1 to 3000 vaccinations to 1 to 35,000 vaccinations. Various other preparations involving neural tissues continue to be associated with encephalomyelitis. Introduction of nonneural tissue vaccines, particularly human diploid cell vaccine, have markedly reduced but not eliminated the neurologic complications (17). Cases of encephalitis, radiculitis, and acute inflammatory demyelinating polyradiculoneuropathy have been reported following rabies vaccination containing neural elements.

Antitetanus vaccine. Antitetanus vaccination is generally safe but adverse effects such as neuropathy may occur. History of such vaccination should be considered in the differential diagnosis of neuropathies. An elderly person was reported to develop tetraplegia due to polyneuropathy within a few hours following antitetanus vaccination (35).

Japanese encephalitis vaccine. The Japanese encephalitis vaccine has been used for childhood immunization programs in Asia since the 1960s and is generally considered to be safe. Neurologic side effects reported in larger vaccine trials in Asia range from 1 to 2.3 per million vaccines. A few patients have been reported to develop severe encephalitis-like illness with MRI changes, indicating acute disseminated encephalomyelitis. Similar findings have been reported in naturally occurring Japanese B encephalitis. A review of the adverse event reports following Japanese encephalitis vaccination in the United States from 1999 to 2009 revealed no reports of encephalitis, meningitis, or Guillain-Barré syndrome (25).

Oral poliomyelitis vaccine. Using a description of a child with acute flaccid paralysis possibly caused by a poliovirus vaccine, the authors reviewed the literature and stated that oral poliomyelitis vaccine and type 2 serotype poliomyelitis virus vaccine were the risk factors for vaccine-associated paralytic poliomyelitis (51). Moreover, the combination of 2 vaccines was associated with an increased risk of acute disseminated encephalomyelitis and flaccid paralysis following immunization when compared with the administration of vaccines separately. The risk of paralytic poliomyelitis resulting from polio vaccine as presented by these authors is not convincing.

Tick-borne encephalitis. Adverse neurologic reactions after tick-borne vaccination are rare and reversible. Most frequently reported adverse events are headache, neuropathy, and meningeal irritation.

DNA vaccines. Even though the DNA is not injected with adjuvant, induction of antibodies to DNA is always a possibility and might depend on the sequences found in the injected plasmid. However, the results obtained to date have indicated that high levels of high affinity antibodies are not induced. In addition, it has been shown that plasmid DNA can be reinjected at later times to boost the immune response. This suggests that any immune response to the DNA that might occur is not able to block the effect of subsequent injections of DNA.

RNA vaccines. Acute reactions following COVID-19 vaccination include anaphylaxis that requires immediate epinephrine injection for management. The cause is the activation of mast cells through antigen binding and crosslinking of IgE. The mRNA vaccines for COVID-19 use a lipid-based nanoparticle carrier system that prevents the rapid enzymatic degradation of mRNA and facilitates in vivo delivery. This lipid-based nanoparticle carrier system is further stabilized by a polyethylene glycol (PEG) 2000 lipid conjugate that prolongs half-life. It is possible that some populations are at higher risk for non-IgE-mediated mast cell activation (06). Another nonimmune reaction is vasovagal syncope.

Miscellaneous neurologic complications. Various reported neurologic complications not listed above include Guillain-Barre syndrome following influenza vaccine and seizures following pertussis vaccination. In a study from China, a total of 89.6 million doses of influenza A (H1N1) vaccine were administered from 2009 to 2010, and only 11 cases of the Guillain-Barré syndrome were reported as adverse events, ie, a rate of 0.1 per 1 million doses, which is lower than the background incidence of this syndrome in China (24). Rigorous scientific studies have not identified links between autism and the measles, mumps, and rubella vaccine as alleged previously in some publications (30).

Several case reports of the onset or exacerbation of multiple sclerosis or other demyelinating conditions shortly after vaccination have suggested that vaccines may increase the risk of demyelinating diseases. One report concerns an army officer who received 20 vaccinations and boosters (hypervaccination) during the period 2000 to 2006 in the Balkans and was subsequently diagnosed with multiple sclerosis in 2008 (55). However, case-control studies have not shown that vaccination against hepatitis B, influenza, tetanus, measles, or rubella is associated with an increased risk of multiple sclerosis.

A strong association was found between the inactivated intranasal influenza vaccine used in Switzerland and Bell palsy. Therefore, this vaccine was withdrawn from clinical use. Four cases of Bell palsy were reported as adverse events in thousands of patients in a clinical trial of COVID-19 mRNA vaccine BNT162b2 (37). When uncommon side effects that are prevalent in the general population are observed, the question of whether they were truly vaccine-related remains to be determined.

There is a suggestion that the inflammatory response of amyloid beta vaccination in Alzheimer disease is related to dose. A low dose of vaccine with a rather small peptide or low levels of antibodies would help to keep the inflammatory response as low as possible.

A 3- to 4-fold increased risk of narcolepsy in vaccinated children and adolescents, verified by epidemiological studies, was reported with use of Pandemrix pandemic influenza vaccine in Sweden (11). Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy.

Special considerations

Live virus vaccines should not be administered during pregnancy because of the potential risk to the fetus. However, other immunizations are often avoided in pregnancy and the early postpartum period because of the mistaken belief that vaccines are harmful to the fetus or neonate. The protective effect of maternal antibody against many viral diseases has been recognized, and the use of maternal immunization has been considered for augmenting this protection in the young infant. Advantages of maternal immunization include the following:

	• Prevention of congenital neonatal infections.
	• IgG antibodies cross the placenta wall during the third trimester so that immunization of the pregnant women protects the infants who remain highly susceptible to infections but are the least responsive to vaccines given directly.

Disadvantages of maternal vaccination are:

	• Potential inhibition of an infant's response to active immunization or natural infection.
	• Liability issues with pharmaceutical companies and physicians.

Immunization of pregnant women with viral vaccines for poliovirus, influenza viruses, and rubella has been found to be safe for both the mother and the fetus. The efficacy of the rubella vaccine has not been proven, and it is used only during pregnancy with rubella titers.

Scientific basis

	• Brain parenchyma has a functional type I interferon response that limits spread of infection and is relevant to design of vaccines for viral infections of the brain.
	• The goal of vaccination is to induce an immune response to prevent infection or limit the effects of infection, which is more effective and durable than the natural response to an infection.

The brain is an immune privileged organ based on differences between the innate and adaptive immune responses of the brain as compared to those of other organs. However, the brain parenchyma has a functional type I interferon (IFN) response that can limit spread of vesicular stomatitis virus (VSV) at the inoculation site as well as among synaptically connected neurons (10). Moreover, the infected microglia produce type I interferon, and uninfected microglia induce an innate immune response following virus injection, which can limit viral spread. This finding has implications for design of vaccines for viral diseases involving the brain.

The main aim of vaccination is the induction of an immune response designed to prevent infection or limit the effects of infection. Vaccination differs from natural or innate immune protection against infection in 2 ways. First, in pathogen-specific immune response induced by a vaccine, both the humoral (antibody-mediated) and cellular arms of the immune system are involved, whereas the phagocytes and cytokines participate in natural protection against infection. Second, the immune response induced by a vaccine is more durable (months to years) and takes place before exposure to the infection.