- Email: [email protected]
Smallpox vaccines: from first to second to third generation
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Juvela S, Heiskanen O, Poranen A, et al. The treatment of spontaneous intracerebral hemorrhage. J Neurosurg 1989; 70: 755–58. Batjer HH, Reisch JS, Allen BC, et al. Failure of surgery to improve outcome in hypertensive putaminal hemorrhage. Arch Neurol 1990; 47: 1103–06. Morgenstern LB, Frankowski RF, Shedden P, et al. Surgical treatment for intracerebral hemorrhage (STICH). Neurology 1998; 51: 1359–63. Zuccarello M, Brott T, Derex L, et al. Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Stroke 1999; 30: 1833–39. Tan SH, Ng PY, Yeo TT, et al. Hypertensive basal ganglia hemorrhage: a prospective study comparing surgical and nonsurgical management. Surg Neurol 2001; 56: 287–93. Hankey GJ, Hon C. Surgery for primary intracerebral hemorrhage: is it safe
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and effective? A systemic review of case series and randomized trials. Stroke 1997; 28: 2126–32. Prasad K, Browman G, Srivastava A, et al. Surgery in primary supratentorial intracerebral hematoma: a meta-analysis of randomized trials. Acta Neurol Scand 1997; 95: 103–10. Fernandes HM, Gregson B, Siddique S, Mendelow AD. Surgery in intracerebral hemorrhage: the uncertainty continues. Stroke 2000; 31: 2511–16. Wagner KR, Xi G, Hua Y, et al. Clot removal following lysis with tissue plasminogen activator markedly reduces perihematomal edema in an intracerebral hemorrhage model. Stroke 1996; 27: 183. Nakano T, Ohkuma H, Ebina K, Suzuki S. Neuroendoscopic surgery for intracerebral haemorrhage: comparison with traditional therapies. Minim Invas Neurosurg 2003; 46: 278–83.
Smallpox vaccines: from first to second to third generation See Articles page 398
In this issue of The Lancet, Richard Greenberg and colleagues report a trial that compared a new smallpox vaccine derived from cell culture with a vaccine derived from calf lymph. Their report is timely, given current concerns over biological weapons. The smallpox vaccines currently licensed in the USA and UK are live, attenuated vaccinia virus derived from calf lymph. Although this type of vaccine was used to eradicate smallpox worldwide, well-documented safety limitations prevent its widespread use in a civilian population without an outbreak. Historically, out of every million people vaccinated for smallpox, 14–52 people had serious or life-threatening adverse reactions to the vaccine, and one
Wellcome Library, London
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Jenner inoculating patients against smallpox
362
to two people per million primary vaccinees died because of the vaccine.1 Serious side-effects include eczema vaccinatum, progressive vaccinia, postvaccinal encephalitis, fetal vaccinia, vaccinia keratitis, and myopericarditis. There were also cases of inadvertent self-inoculation and vaccinated people transmitting vaccinia vaccine virus to others.2 Also, smallpox vaccine is contraindicated in up to 30% or more of the population, including infants, pregnant women or women who are breastfeeding infants, the immunocompromised, those with eczema or exfoliative skin disorders, people who live in the same house or are in intimate contact with people with the above conditions, and people with cardiovascular conditions (such as a history of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischaemic attack, chest pain or shortness of breath with activity, or any cardiac condition under the care of a physician).3,4 In their trial, Greenberg and colleagues randomly allocated 350 healthy adults to receive cell-cultured smallpox vaccine (CCSV) or calf-lymph-derived vaccine (Dryvax). Participants included 150 vaccinia-naive people 18–30 years of age, and 100 participants who were not naive to vaccinia and 32–65 years of age. A further 100 vaccinia-naive people 18–30 years of age received one of five CCSV doses of various dilutions in a single-blind manner. To assess safety and immunogenicity, researchers made physical examinations, recorded adverse events and take-rates, and performed neutralisation antibody titres, T-cell proliferative-response assays, and interferon- Elispot. The last two assays were designed to measure cellmediated immunity. All but one participant developed pock lesions. Vaccineassociated adverse reactions were similar between the CCSV and Dryvax recipients. Although none of the participants had serious vaccine-related adverse events, the vaccinenaive recipients had the expected side-effects: erythema, axillary adenopathy, swelling, pain, and lymphangitis. The number of participants who became immune to the virus was high, although antibody seroconversion rates were lower in CCSV recipients, while measures of cell-mediated www.thelancet.com Vol 365 January 29, 2005
Comment
immunity were higher in CCSV recipients. Diluted vaccines conferred immunity generally as effectively as undiluted vaccines in both vaccinia-naive and non-naive groups. These results show that the CCSV vaccine is equally immunogenic and safe in both groups compared with calflymph-derived vaccine. Greenberg and colleagues’ study shows that an immunogenic second-generation smallpox vaccine (CCSV) can be developed, manufactured, and presumably licensed. Solving the shortage of smallpox vaccine would improve our defence against biological weapons. Vaccine availability is a problem because existing stocks are more than 20 years old and in limited supply. Also, such a second-generation vaccine eliminates concerns related to calf-lymph-derived vaccines, such as contamination by bovine prions (ie, bovine spongiform encephalopathy), and unwanted immune responses to bovine and other non-vaccinia entities in the vaccine. Researchers derive CCSV by growing vaccinia virus in human diploid fetal lung fibroblasts, which prevents cross-species contamination and allows viral growth under aseptic conditions. Greenberg and colleagues’ results represent an incremental advance in smallpox vaccinology. However, we need third-generation vaccines to provide both long-lasting immunity and enhanced safety. Although the CCSV vaccine provides distinct advantages, we still must discover how to provide universal pre-exposure immunity to smallpox. Because of contraindications and safety concerns, the public probably will not accept the
use of CCSV or Dryvax unless there is a documented case of smallpox. However, a safe, immunogenic, effective, and universally administered vaccine would provide a barrier against attempts to use smallpox as a weapon. Therefore, research leading to third-generation vaccines, such as vaccinia viruses that are further attenuated, inactivated viruses, or, more promising, subunit or peptide-based vaccines with or without adjuvants, should remain a significant goal of public health.5
Gregory A Poland Mayo Vaccine Research Group and Program in Translational Immunovirology and Biodefense, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA [email protected] I was an investigator on a previous smallpox vaccine clinical trial funded by Acambis. I thank Kim Zabel for editorial assistance. 1 2
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4
5
Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968. N Engl J Med 1969; 281: 1201–08. Centers for Disease Control and Prevention. Update: adverse events following civilian smallpox vaccination—United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52: 475–77. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA 2003; 289: 3283–89. Centers for Disease Contol and Prevention. Smallpox (vaccinia) vaccine contraindications. 2004: http://www.bt.cdc.gov/agent/ smallpox/ vaccination/contraindications-clinic.asp (accessed Oct 1, 2004). Poland GA, Neff JM. Smallpox vaccines: problems and prospects. In: Poland GA, ed. Immunology and allergy clinics of North America: vaccines in the 21st century. Philadelphia: WB Saunders, 2003: 731–43.
How much does dardarin contribute to Parkinson’s disease? In today’s Lancet, William Nichols, William Gilks, Alessio Di Fonzo, and their respective colleagues report the identification of a Gly2019Ser mutation in the LRRK2 gene. This mutation accounts for a surprisingly high proportion of both familial and isolated cases of Parkinson’s disease. LRRK2 is the last born of the series of genes responsible for monogenic (autosomal dominant or autosomal recessive) Parkinson’s disease, a saga that began only in 1997. Until now, the genes involved in autosomal recessive Parkinson’s disease were Parkin, DJ-1, and Pink1 and, in autosomal dominant forms, -synuclein, UCHL1, and NR4A2.1 However, definite genetic proof of the causative nature of the latter two (UCH1 and NR4A2) is still lacking. A new chapter began in 2002, when the PARK8 locus was first mapped to chromosome 12p in a single Japanese family.2 The mapping was then confirmed in at least two families from Canada and the USA, suggesting that it is a frequent occurrence in autosomal dominant Parkinson’s disease.3 Very recently, the corresponding gene, LRRK2, was identified independently by two groups4,5 who reported seven different mis-sense mutations. www.thelancet.com Vol 365 January 29, 2005
The finding of LRRK2 is novel in several respects. First, the protein encoded by LRRK2, dardarin—a term derived from dardara, the Basque word for tremor—contains several domains including the catalytic domain of a tyrosine kinase. From the genes known to cause Parkinson’s disease, it has been suggested that abnormal protein aggregation (-synuclein), dysfunction of the ubiquitinproteasome protein-degradation pathway (Parkin and UCHL1), oxidative stress (DJ-1), and mitochondrial dysfunction (Pink1) contribute to pathogenesis. Dardarin is the first kinase to be implicated in Parkinson’s disease. Second, although the clinical features of patients with LRRK2 mutations are typical of Parkinson’s disease, the neuropathology is highly variable. The age at onset varies between 35 and 78 years, but all patients present the cardinal features of the disease (rigidity, bradykinesia, resting tremor with unilateral onset) associated with a good response to levodopa and frequent treatment-induced dyskinesias. By contrast, although the dopaminergic neurons in the substantia nigra degenerate in all cases in association with gliosis, the pathological markers of the
Published online January 18, 2005. http://image.thelancet.com/ extras/04cmt455web.pdf See Research Letters pages 410, 412, and 415
363
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5 6
7
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Juvela S, Heiskanen O, Poranen A, et al. The treatment of spontaneous intracerebral hemorrhage. J Neurosurg 1989; 70: 755–58. Batjer HH, Reisch JS, Allen BC, et al. Failure of surgery to improve outcome in hypertensive putaminal hemorrhage. Arch Neurol 1990; 47: 1103–06. Morgenstern LB, Frankowski RF, Shedden P, et al. Surgical treatment for intracerebral hemorrhage (STICH). Neurology 1998; 51: 1359–63. Zuccarello M, Brott T, Derex L, et al. Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Stroke 1999; 30: 1833–39. Tan SH, Ng PY, Yeo TT, et al. Hypertensive basal ganglia hemorrhage: a prospective study comparing surgical and nonsurgical management. Surg Neurol 2001; 56: 287–93. Hankey GJ, Hon C. Surgery for primary intracerebral hemorrhage: is it safe
9
10
11
12
and effective? A systemic review of case series and randomized trials. Stroke 1997; 28: 2126–32. Prasad K, Browman G, Srivastava A, et al. Surgery in primary supratentorial intracerebral hematoma: a meta-analysis of randomized trials. Acta Neurol Scand 1997; 95: 103–10. Fernandes HM, Gregson B, Siddique S, Mendelow AD. Surgery in intracerebral hemorrhage: the uncertainty continues. Stroke 2000; 31: 2511–16. Wagner KR, Xi G, Hua Y, et al. Clot removal following lysis with tissue plasminogen activator markedly reduces perihematomal edema in an intracerebral hemorrhage model. Stroke 1996; 27: 183. Nakano T, Ohkuma H, Ebina K, Suzuki S. Neuroendoscopic surgery for intracerebral haemorrhage: comparison with traditional therapies. Minim Invas Neurosurg 2003; 46: 278–83.
Smallpox vaccines: from first to second to third generation See Articles page 398
In this issue of The Lancet, Richard Greenberg and colleagues report a trial that compared a new smallpox vaccine derived from cell culture with a vaccine derived from calf lymph. Their report is timely, given current concerns over biological weapons. The smallpox vaccines currently licensed in the USA and UK are live, attenuated vaccinia virus derived from calf lymph. Although this type of vaccine was used to eradicate smallpox worldwide, well-documented safety limitations prevent its widespread use in a civilian population without an outbreak. Historically, out of every million people vaccinated for smallpox, 14–52 people had serious or life-threatening adverse reactions to the vaccine, and one
Wellcome Library, London
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Jenner inoculating patients against smallpox
362
to two people per million primary vaccinees died because of the vaccine.1 Serious side-effects include eczema vaccinatum, progressive vaccinia, postvaccinal encephalitis, fetal vaccinia, vaccinia keratitis, and myopericarditis. There were also cases of inadvertent self-inoculation and vaccinated people transmitting vaccinia vaccine virus to others.2 Also, smallpox vaccine is contraindicated in up to 30% or more of the population, including infants, pregnant women or women who are breastfeeding infants, the immunocompromised, those with eczema or exfoliative skin disorders, people who live in the same house or are in intimate contact with people with the above conditions, and people with cardiovascular conditions (such as a history of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischaemic attack, chest pain or shortness of breath with activity, or any cardiac condition under the care of a physician).3,4 In their trial, Greenberg and colleagues randomly allocated 350 healthy adults to receive cell-cultured smallpox vaccine (CCSV) or calf-lymph-derived vaccine (Dryvax). Participants included 150 vaccinia-naive people 18–30 years of age, and 100 participants who were not naive to vaccinia and 32–65 years of age. A further 100 vaccinia-naive people 18–30 years of age received one of five CCSV doses of various dilutions in a single-blind manner. To assess safety and immunogenicity, researchers made physical examinations, recorded adverse events and take-rates, and performed neutralisation antibody titres, T-cell proliferative-response assays, and interferon- Elispot. The last two assays were designed to measure cellmediated immunity. All but one participant developed pock lesions. Vaccineassociated adverse reactions were similar between the CCSV and Dryvax recipients. Although none of the participants had serious vaccine-related adverse events, the vaccinenaive recipients had the expected side-effects: erythema, axillary adenopathy, swelling, pain, and lymphangitis. The number of participants who became immune to the virus was high, although antibody seroconversion rates were lower in CCSV recipients, while measures of cell-mediated www.thelancet.com Vol 365 January 29, 2005
Comment
immunity were higher in CCSV recipients. Diluted vaccines conferred immunity generally as effectively as undiluted vaccines in both vaccinia-naive and non-naive groups. These results show that the CCSV vaccine is equally immunogenic and safe in both groups compared with calflymph-derived vaccine. Greenberg and colleagues’ study shows that an immunogenic second-generation smallpox vaccine (CCSV) can be developed, manufactured, and presumably licensed. Solving the shortage of smallpox vaccine would improve our defence against biological weapons. Vaccine availability is a problem because existing stocks are more than 20 years old and in limited supply. Also, such a second-generation vaccine eliminates concerns related to calf-lymph-derived vaccines, such as contamination by bovine prions (ie, bovine spongiform encephalopathy), and unwanted immune responses to bovine and other non-vaccinia entities in the vaccine. Researchers derive CCSV by growing vaccinia virus in human diploid fetal lung fibroblasts, which prevents cross-species contamination and allows viral growth under aseptic conditions. Greenberg and colleagues’ results represent an incremental advance in smallpox vaccinology. However, we need third-generation vaccines to provide both long-lasting immunity and enhanced safety. Although the CCSV vaccine provides distinct advantages, we still must discover how to provide universal pre-exposure immunity to smallpox. Because of contraindications and safety concerns, the public probably will not accept the
use of CCSV or Dryvax unless there is a documented case of smallpox. However, a safe, immunogenic, effective, and universally administered vaccine would provide a barrier against attempts to use smallpox as a weapon. Therefore, research leading to third-generation vaccines, such as vaccinia viruses that are further attenuated, inactivated viruses, or, more promising, subunit or peptide-based vaccines with or without adjuvants, should remain a significant goal of public health.5
Gregory A Poland Mayo Vaccine Research Group and Program in Translational Immunovirology and Biodefense, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA [email protected] I was an investigator on a previous smallpox vaccine clinical trial funded by Acambis. I thank Kim Zabel for editorial assistance. 1 2
3
4
5
Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968. N Engl J Med 1969; 281: 1201–08. Centers for Disease Control and Prevention. Update: adverse events following civilian smallpox vaccination—United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52: 475–77. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA 2003; 289: 3283–89. Centers for Disease Contol and Prevention. Smallpox (vaccinia) vaccine contraindications. 2004: http://www.bt.cdc.gov/agent/ smallpox/ vaccination/contraindications-clinic.asp (accessed Oct 1, 2004). Poland GA, Neff JM. Smallpox vaccines: problems and prospects. In: Poland GA, ed. Immunology and allergy clinics of North America: vaccines in the 21st century. Philadelphia: WB Saunders, 2003: 731–43.
How much does dardarin contribute to Parkinson’s disease? In today’s Lancet, William Nichols, William Gilks, Alessio Di Fonzo, and their respective colleagues report the identification of a Gly2019Ser mutation in the LRRK2 gene. This mutation accounts for a surprisingly high proportion of both familial and isolated cases of Parkinson’s disease. LRRK2 is the last born of the series of genes responsible for monogenic (autosomal dominant or autosomal recessive) Parkinson’s disease, a saga that began only in 1997. Until now, the genes involved in autosomal recessive Parkinson’s disease were Parkin, DJ-1, and Pink1 and, in autosomal dominant forms, -synuclein, UCHL1, and NR4A2.1 However, definite genetic proof of the causative nature of the latter two (UCH1 and NR4A2) is still lacking. A new chapter began in 2002, when the PARK8 locus was first mapped to chromosome 12p in a single Japanese family.2 The mapping was then confirmed in at least two families from Canada and the USA, suggesting that it is a frequent occurrence in autosomal dominant Parkinson’s disease.3 Very recently, the corresponding gene, LRRK2, was identified independently by two groups4,5 who reported seven different mis-sense mutations. www.thelancet.com Vol 365 January 29, 2005
The finding of LRRK2 is novel in several respects. First, the protein encoded by LRRK2, dardarin—a term derived from dardara, the Basque word for tremor—contains several domains including the catalytic domain of a tyrosine kinase. From the genes known to cause Parkinson’s disease, it has been suggested that abnormal protein aggregation (-synuclein), dysfunction of the ubiquitinproteasome protein-degradation pathway (Parkin and UCHL1), oxidative stress (DJ-1), and mitochondrial dysfunction (Pink1) contribute to pathogenesis. Dardarin is the first kinase to be implicated in Parkinson’s disease. Second, although the clinical features of patients with LRRK2 mutations are typical of Parkinson’s disease, the neuropathology is highly variable. The age at onset varies between 35 and 78 years, but all patients present the cardinal features of the disease (rigidity, bradykinesia, resting tremor with unilateral onset) associated with a good response to levodopa and frequent treatment-induced dyskinesias. By contrast, although the dopaminergic neurons in the substantia nigra degenerate in all cases in association with gliosis, the pathological markers of the
Published online January 18, 2005. http://image.thelancet.com/ extras/04cmt455web.pdf See Research Letters pages 410, 412, and 415
363