Nasal Vaccination, Escherichia coli Enterotoxin, and Bell's Palsy
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《新英格兰医药杂志》
In 1997, a Swiss Company (Berna Biotech) received approval to market an inactivated influenza vaccine for parenteral administration that consists of the hemagglutinin and neuraminidase surface antigens of influenzavirus incorporated into liposomes. This virosome vaccine was subsequently used in the formulation of an influenzavirus vaccine for intranasal administration. To optimize both mucosal and systemic immune responses to the nasal vaccine, heat-labile Escherichia coli enterotoxin, one of the most powerful mucosal adjuvants known, was included in the formulation. The clinical studies showed that clinically significant antibody responses to influenzavirus were elicited by this vaccine, as evidenced in both nasopharyngeal secretions and serum, and that the vaccine was protective against influenza in both adults and children. Approval of the vaccine for distribution and use in Switzerland followed.
After Bell's palsy was identified in some recipients of this intranasal vaccine, however, it was withdrawn from the market. The report by Mutsch et al. in this issue of the Journal (pages 896–903) presents very strong evidence that the occurrence of Bell's palsy resulted from the use of the vaccine. The strong relation in the case–control study is supported by the case-series analysis that identified an increase in incidence, with a peak occurring between 31 and 60 days after vaccination and then a return to the base-line level of risk. Since the vaccine contained more than inactivated influenzavirus, it is important to consider the reasons for the increased risk of Bell's palsy. Nevertheless, the finding indicates a problem for nasal vaccination, which is an evolving approach to the prevention of influenza and other infectious diseases.
Is there cause for concern about the use of the current influenza vaccines? The results of the study indicate clearly that the parenteral use of inactivated influenza vaccine did not confer an increased risk of Bell's palsy. Thus, the current public health procedure of administering inactivated influenza vaccine parenterally for the prevention of influenza and its complications is not threatened by the finding. Is there cause for concern about the use of the new live attenuated vaccine (FluMist), which is given intranasally? Although some variation in the prevalence of Bell's palsy has been reported, it does not appear to occur in a seasonal pattern, and no relationship between its occurrence and influenza epidemics has been described. Since natural influenzavirus infection does not appear to be a precipitating event for Bell's palsy, there is no reason to suppose that an attenuated infection induced by a live vaccine such as the intranasal vaccine would confer an increased risk of this condition. Thus, there is little reason for concern about the continued use of the new live influenzavirus vaccine.
There is a need for improvement in the protection afforded by the current inactivated influenza vaccines, and intranasal vaccination is one possible alternative. Of greater concern than the development of alternative influenza vaccines, however, is the future of intranasal vaccination as an option for the prevention of infectious disease. Many consider the nasal route to be the most effective route for inducing both mucosal and systemic immunity to an infectious agent and believe that the exploitation of the advantages of this route of administration will be the basis for the next generation of vaccines. An awareness of these advantages for the administration of antigens (see Table) has led to repeated demonstrations in animals and humans of the potential value of intranasal vaccines for the prevention of at least 10 viral infections, 10 bacterial infections, and 2 parasitic infections. The requirement that a mucosal adjuvant be incorporated into the vaccine in order to elicit optimal responses has led to the demonstration of the value of about 10 different adjuvants. Thus, the effort involved in developing intranasal vaccines is extensive.
Table. Advantages and Disadvantage of Intranasal Vaccinations.
Elucidating the pathogenesis of the Bell's palsy that occurred after the administration of the Berna intranasal vaccine is a high priority for those involved in vaccine development. Was the increased risk attributable to the inactivated influenzavirus, the E. coli enterotoxin, both of these components, the route of administration, or some other factor? Since parenteral administration of influenza vaccine did not confer a similar risk, inactivated influenzavirus was not the cause. The authors sought but did not identify another factor that might have had a contributing effect; therefore, the E. coli toxin, the combination of influenzavirus and the toxin, or the route of administration remain the most likely possibilities. Given that the respiratory tract of humans is challenged with antigens almost on a daily basis and that frequent viral and bacterial infections, carriage of bacterial antigens, and inert environmental antigens induce numerous host responses, including immune responses, it seems unlikely that the intranasal administration of inactivated influenzavirus would elicit a qualitatively or quantitatively unique response that would precipitate the characteristic inflammatory seventh-nerve response of Bell's palsy. There are data, however, suggesting that the E. coli enterotoxin in the vaccine may be the risk-inducing factor.
Cholera toxin and heat-labile E. coli enterotoxin are very potent mucosal adjuvants; the B subunit of these toxins binds to gangliosides on the cell surface, leading to internalization, and the A subunit is responsible for the activation of adenyl cyclase, elevated cyclic AMP levels, and the water and chloride secretion that leads to diarrhea during intestinal infection. Both the A and B subunits exert adjuvant effects through a variety of actions. After the intranasal administration of antigen in mice, both antigen and toxin were found in the olfactory nerve and the olfactory bulb for an extended period; antigen accumulation did not occur in the absence of toxin. In addition, the intranasal enterotoxin induced inflammatory responses in the olfactory sites and the meninges of mice. Thus, there is a reason to be concerned about neurotoxic effects of the intranasal administration of a vaccine containing an enterotoxin adjuvant.
What intranasally induced responses led to Bell's palsy? The fact that the interval of maximal occurrence in the Mutsch study was 31 to 60 days after vaccination suggests that an induced response, rather than some direct toxic effect, led to the palsy. The prevailing notion is that most cases of Bell's palsy represent an autoimmune disorder or a reactivation of a latent herpesvirus infection. Both herpes simplex virus and varicella–zoster virus have been shown to be latent in a high proportion of seventh-nerve ganglia. The well-known Ramsay Hunt syndrome involves the reactivation of varicella–zoster virus, with a resulting seventh-nerve palsy and local cutaneous lesions. Herpes simplex virus is less well established as a cause of Bell's palsy, but the evidence of a causal relation is strong, and it is possible that a herpesvirus infection was reactivated in the patients in whom the palsy developed. Identification of the cause of Bell's palsy associated with the use of the intranasal E. coli–adjuvant influenza vaccine and other intranasal vaccines is needed to facilitate further development of intranasal vaccines, including vaccines for influenza.
Source Information
From the Baylor College of Medicine, Houston.(Robert B. Couch, M.D.)
After Bell's palsy was identified in some recipients of this intranasal vaccine, however, it was withdrawn from the market. The report by Mutsch et al. in this issue of the Journal (pages 896–903) presents very strong evidence that the occurrence of Bell's palsy resulted from the use of the vaccine. The strong relation in the case–control study is supported by the case-series analysis that identified an increase in incidence, with a peak occurring between 31 and 60 days after vaccination and then a return to the base-line level of risk. Since the vaccine contained more than inactivated influenzavirus, it is important to consider the reasons for the increased risk of Bell's palsy. Nevertheless, the finding indicates a problem for nasal vaccination, which is an evolving approach to the prevention of influenza and other infectious diseases.
Is there cause for concern about the use of the current influenza vaccines? The results of the study indicate clearly that the parenteral use of inactivated influenza vaccine did not confer an increased risk of Bell's palsy. Thus, the current public health procedure of administering inactivated influenza vaccine parenterally for the prevention of influenza and its complications is not threatened by the finding. Is there cause for concern about the use of the new live attenuated vaccine (FluMist), which is given intranasally? Although some variation in the prevalence of Bell's palsy has been reported, it does not appear to occur in a seasonal pattern, and no relationship between its occurrence and influenza epidemics has been described. Since natural influenzavirus infection does not appear to be a precipitating event for Bell's palsy, there is no reason to suppose that an attenuated infection induced by a live vaccine such as the intranasal vaccine would confer an increased risk of this condition. Thus, there is little reason for concern about the continued use of the new live influenzavirus vaccine.
There is a need for improvement in the protection afforded by the current inactivated influenza vaccines, and intranasal vaccination is one possible alternative. Of greater concern than the development of alternative influenza vaccines, however, is the future of intranasal vaccination as an option for the prevention of infectious disease. Many consider the nasal route to be the most effective route for inducing both mucosal and systemic immunity to an infectious agent and believe that the exploitation of the advantages of this route of administration will be the basis for the next generation of vaccines. An awareness of these advantages for the administration of antigens (see Table) has led to repeated demonstrations in animals and humans of the potential value of intranasal vaccines for the prevention of at least 10 viral infections, 10 bacterial infections, and 2 parasitic infections. The requirement that a mucosal adjuvant be incorporated into the vaccine in order to elicit optimal responses has led to the demonstration of the value of about 10 different adjuvants. Thus, the effort involved in developing intranasal vaccines is extensive.
Table. Advantages and Disadvantage of Intranasal Vaccinations.
Elucidating the pathogenesis of the Bell's palsy that occurred after the administration of the Berna intranasal vaccine is a high priority for those involved in vaccine development. Was the increased risk attributable to the inactivated influenzavirus, the E. coli enterotoxin, both of these components, the route of administration, or some other factor? Since parenteral administration of influenza vaccine did not confer a similar risk, inactivated influenzavirus was not the cause. The authors sought but did not identify another factor that might have had a contributing effect; therefore, the E. coli toxin, the combination of influenzavirus and the toxin, or the route of administration remain the most likely possibilities. Given that the respiratory tract of humans is challenged with antigens almost on a daily basis and that frequent viral and bacterial infections, carriage of bacterial antigens, and inert environmental antigens induce numerous host responses, including immune responses, it seems unlikely that the intranasal administration of inactivated influenzavirus would elicit a qualitatively or quantitatively unique response that would precipitate the characteristic inflammatory seventh-nerve response of Bell's palsy. There are data, however, suggesting that the E. coli enterotoxin in the vaccine may be the risk-inducing factor.
Cholera toxin and heat-labile E. coli enterotoxin are very potent mucosal adjuvants; the B subunit of these toxins binds to gangliosides on the cell surface, leading to internalization, and the A subunit is responsible for the activation of adenyl cyclase, elevated cyclic AMP levels, and the water and chloride secretion that leads to diarrhea during intestinal infection. Both the A and B subunits exert adjuvant effects through a variety of actions. After the intranasal administration of antigen in mice, both antigen and toxin were found in the olfactory nerve and the olfactory bulb for an extended period; antigen accumulation did not occur in the absence of toxin. In addition, the intranasal enterotoxin induced inflammatory responses in the olfactory sites and the meninges of mice. Thus, there is a reason to be concerned about neurotoxic effects of the intranasal administration of a vaccine containing an enterotoxin adjuvant.
What intranasally induced responses led to Bell's palsy? The fact that the interval of maximal occurrence in the Mutsch study was 31 to 60 days after vaccination suggests that an induced response, rather than some direct toxic effect, led to the palsy. The prevailing notion is that most cases of Bell's palsy represent an autoimmune disorder or a reactivation of a latent herpesvirus infection. Both herpes simplex virus and varicella–zoster virus have been shown to be latent in a high proportion of seventh-nerve ganglia. The well-known Ramsay Hunt syndrome involves the reactivation of varicella–zoster virus, with a resulting seventh-nerve palsy and local cutaneous lesions. Herpes simplex virus is less well established as a cause of Bell's palsy, but the evidence of a causal relation is strong, and it is possible that a herpesvirus infection was reactivated in the patients in whom the palsy developed. Identification of the cause of Bell's palsy associated with the use of the intranasal E. coli–adjuvant influenza vaccine and other intranasal vaccines is needed to facilitate further development of intranasal vaccines, including vaccines for influenza.
Source Information
From the Baylor College of Medicine, Houston.(Robert B. Couch, M.D.)