Correspondence
with OspA antigen. However, because of such mistaken perceptions, we removed the putative arthritogenic OspA epitope in the new multivalent vaccine, as described and discussed in our manuscript.2 We believe, on the basis of the data generated in our phase 1/2 trial and from other studies of OspA vaccines, that the new multivalent OspA vaccine could have a major effect on public health by preventing a highly prevalent and potentially debilitating disease. All authors are employees of Baxter. PNB, BAC, NW, and GA own stock and share options in Baxter, and have planned, pending, or issued patents for Lyme vaccines.
*P Noel Barrett, Brian A Crowe, Nina Wressnigg, Daniel Portsmouth, Gerald Aichinger [email protected] Vaccine R&D, Biomedical Research Centre, Baxter Bioscience, Uferstraße 15, A-2304 Orth/Donau, Austria (PNB, BAC, DP); and Vaccine R&D, Baxter Bioscience, Vienna, Austria (NW, GA) 1
2
3
4
Wressnigg N, Pollabauer EM, Aichinger G, et al. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. Lancet Infect Dis 2013; 13: 680–89. Lathrop SL, Ball R, Haber P, et al. Adverse event reports following vaccination for Lyme disease: December 1998–July 2000. Vaccine 2002; 20: 1603–08. Ball R, Shadomy SV, Meyer A, et al. HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination. Arthritis Rheum 2009; 60: 1179–86. Steere AC, Drouin EE, Glickstein LJ. Relationship between immunity to Borrelia burgdorferi outersurface protein A (OspA) and Lyme arthritis. Clin Infect Dis 2011; 52 (suppl 3): s259–65.
Author’s reply I wholly concur with Raphael Stricker and Lorraine Johnson that attention to safety must be central to the development of any novel therapeutic agent. Comparative safety has certainly been an open topic of discussion with several second generation vaccines, such as those for acellular pertussis, rotavirus, and Japanese encephalitis, which were developed mainly because of safety concerns with their predecessors. This should no doubt be the case for novel Lyme disease vaccines, whether based www.thelancet.com/infection Vol 14 January 2014
on Borrelia burgdorferi outer surface protein A (OspA) or other antigens. My Comment was chiefly a discussion about the future of Lyme disease vaccination, and was intended neither as an autopsy nor eulogy of LYMErix. Nonetheless, I should reiterate that safety concerns about LYMErix were, in fact, never substantiated. Concerns about OspA vaccination arose from observations that HLA-DRB1*0401positive individuals with antibioticrefractory Lyme arthritis (following natural Lyme disease) have strong immune responses to OspA. Subsequent evidence does not substantiate the hypothesis that vaccination with OspA produces this same effect.1 Two clinical trials of the LYMErix vaccine, involving more than 21 000 participants, found that arthritis occurred at the same rate in both vaccine and placebo recipients.2,3 A secondary review of LYMErix by the US Food and Drug Administration in 2001 concluded that arthritis was no more frequent in vaccine recipients than in controls.4 A 2002 examination of the vaccine adverse events reporting system found only 59 cases of arthritis out of 1·4 million vaccine recipients— this prevalence is indistinguishable from the background rate of arthritis in the general population.5 In fact, placebo recipients in the two preapproval trials of the vaccine had a roughly 100-fold higher rate of arthritis. Stricker and Johnson’s selection of small case series must be seen in this context. Case reports by their nature are epistemically incapable of showing causality or quantifying risk. Rare adverse events can, of course, be missed in preapproval trials. Since the lifespan of LYMErix was roughly that of a deer tick, one cannot be sure whether important safety concerns would have ultimately come to light. Nonetheless, the demise of LYMErix seems more to do with headaches at GlaxoSmithKline than with symptoms among its recipients. The phase 1/2 study reported by Nina Wressnigg and colleagues 6 found no major adverse events in 300 recipients of the OspA vaccine. This
finding merits a cautious optimism that the future will hold a new option to safely prevent Lyme disease, a particularly resonant development in light of recent data from the Centers for Disease Control and Prevention suggesting that the disease affects hundreds of thousands of people a year. I declare that I have no conflicts of interest.
Paul M Lantos [email protected] Duke University School of Medicine, DUMC 100800, Durham, NC 27710, USA 1
2
3
4
5
6
Steere AC, Drouin EE, Glickstein LJ. Relationship between immunity to Borrelia burgdorferi outersurface protein A (OspA) and Lyme arthritis. Clin Infect Dis 2011; 52 (suppl 3): s259–65. Sigal LH, Zahradnik JM, Lavin P, et al. A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. N Engl J Med 1998; 339: 216–22. Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998; 339: 209–15. US Food and Drug Administration. LYMErix Lyme disease vaccine, safety update. http:// www.fda.gov/ohrms/dockets/ac/01/briefing/ 3680b2_02.pdf (accessed Nov 2, 2013). Lathrop SL, Ball R, Haber P, et al. Adverse event reports following vaccination for Lyme disease: December 1998–July 2000. Vaccine 2002; 20: 1603–08. Wressnigg N, Pöllabauer E-M, Aichinger G, et al. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. Lancet Infect Dis 2013; 13: 680–89.
Atazanavir-based therapy with pegylated interferon and ribavirin for patients with hepatitis C and HIV Mark Sulkowski and colleagues 1 assessed the safety and efficacy of boceprevir in combination with pegylated interferon alfa-2b (peginterferon) and ribavirin in patients with previously untreated HIV and hepatitis C virus (HCV) genotype 1. The authors showed that adding boceprevir to peginterferon–ribavirin significantly increased the probability of a sustained virological response 13
Correspondence
100
p=0·06
Percentage of patients achieving SVR
80
p=0·0042 60
p=0·052 40
20
0
29
49 Global
55
12
17 IL28B-CC
21
17
32
34
Il28B non-CC
Figure: Sustained virological response rate according to antiretroviral therapy (atazanavir boosted with ritonavir [blue], lopinavir boosted with ritonavir [red], and efavirenz [green]) in patients with HCV genotype 1 and HIV receiving their first pegylated interferon–ribavirin treatment Analysis was done on the whole population and according to IL28B genotype (rs129679860) using χ2 or Fisher´s tests.
(SVR) compared with peginterferon– ribavirin alone.1 In a subanalysis of this trial, we noted that when patients included in the peginterferon–ribavirin control arm were grouped according to antiretroviral regimen, those receiving atazanavir with ritonavir had higher SVR rates than those receiving any another antiretroviral regimen (69% [nine of 13] vs 4·7% [one of 21]; p
with OspA antigen. However, because of such mistaken perceptions, we removed the putative arthritogenic OspA epitope in the new multivalent vaccine, as described and discussed in our manuscript.2 We believe, on the basis of the data generated in our phase 1/2 trial and from other studies of OspA vaccines, that the new multivalent OspA vaccine could have a major effect on public health by preventing a highly prevalent and potentially debilitating disease. All authors are employees of Baxter. PNB, BAC, NW, and GA own stock and share options in Baxter, and have planned, pending, or issued patents for Lyme vaccines.
*P Noel Barrett, Brian A Crowe, Nina Wressnigg, Daniel Portsmouth, Gerald Aichinger [email protected] Vaccine R&D, Biomedical Research Centre, Baxter Bioscience, Uferstraße 15, A-2304 Orth/Donau, Austria (PNB, BAC, DP); and Vaccine R&D, Baxter Bioscience, Vienna, Austria (NW, GA) 1
2
3
4
Wressnigg N, Pollabauer EM, Aichinger G, et al. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. Lancet Infect Dis 2013; 13: 680–89. Lathrop SL, Ball R, Haber P, et al. Adverse event reports following vaccination for Lyme disease: December 1998–July 2000. Vaccine 2002; 20: 1603–08. Ball R, Shadomy SV, Meyer A, et al. HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination. Arthritis Rheum 2009; 60: 1179–86. Steere AC, Drouin EE, Glickstein LJ. Relationship between immunity to Borrelia burgdorferi outersurface protein A (OspA) and Lyme arthritis. Clin Infect Dis 2011; 52 (suppl 3): s259–65.
Author’s reply I wholly concur with Raphael Stricker and Lorraine Johnson that attention to safety must be central to the development of any novel therapeutic agent. Comparative safety has certainly been an open topic of discussion with several second generation vaccines, such as those for acellular pertussis, rotavirus, and Japanese encephalitis, which were developed mainly because of safety concerns with their predecessors. This should no doubt be the case for novel Lyme disease vaccines, whether based www.thelancet.com/infection Vol 14 January 2014
on Borrelia burgdorferi outer surface protein A (OspA) or other antigens. My Comment was chiefly a discussion about the future of Lyme disease vaccination, and was intended neither as an autopsy nor eulogy of LYMErix. Nonetheless, I should reiterate that safety concerns about LYMErix were, in fact, never substantiated. Concerns about OspA vaccination arose from observations that HLA-DRB1*0401positive individuals with antibioticrefractory Lyme arthritis (following natural Lyme disease) have strong immune responses to OspA. Subsequent evidence does not substantiate the hypothesis that vaccination with OspA produces this same effect.1 Two clinical trials of the LYMErix vaccine, involving more than 21 000 participants, found that arthritis occurred at the same rate in both vaccine and placebo recipients.2,3 A secondary review of LYMErix by the US Food and Drug Administration in 2001 concluded that arthritis was no more frequent in vaccine recipients than in controls.4 A 2002 examination of the vaccine adverse events reporting system found only 59 cases of arthritis out of 1·4 million vaccine recipients— this prevalence is indistinguishable from the background rate of arthritis in the general population.5 In fact, placebo recipients in the two preapproval trials of the vaccine had a roughly 100-fold higher rate of arthritis. Stricker and Johnson’s selection of small case series must be seen in this context. Case reports by their nature are epistemically incapable of showing causality or quantifying risk. Rare adverse events can, of course, be missed in preapproval trials. Since the lifespan of LYMErix was roughly that of a deer tick, one cannot be sure whether important safety concerns would have ultimately come to light. Nonetheless, the demise of LYMErix seems more to do with headaches at GlaxoSmithKline than with symptoms among its recipients. The phase 1/2 study reported by Nina Wressnigg and colleagues 6 found no major adverse events in 300 recipients of the OspA vaccine. This
finding merits a cautious optimism that the future will hold a new option to safely prevent Lyme disease, a particularly resonant development in light of recent data from the Centers for Disease Control and Prevention suggesting that the disease affects hundreds of thousands of people a year. I declare that I have no conflicts of interest.
Paul M Lantos [email protected] Duke University School of Medicine, DUMC 100800, Durham, NC 27710, USA 1
2
3
4
5
6
Steere AC, Drouin EE, Glickstein LJ. Relationship between immunity to Borrelia burgdorferi outersurface protein A (OspA) and Lyme arthritis. Clin Infect Dis 2011; 52 (suppl 3): s259–65. Sigal LH, Zahradnik JM, Lavin P, et al. A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. N Engl J Med 1998; 339: 216–22. Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998; 339: 209–15. US Food and Drug Administration. LYMErix Lyme disease vaccine, safety update. http:// www.fda.gov/ohrms/dockets/ac/01/briefing/ 3680b2_02.pdf (accessed Nov 2, 2013). Lathrop SL, Ball R, Haber P, et al. Adverse event reports following vaccination for Lyme disease: December 1998–July 2000. Vaccine 2002; 20: 1603–08. Wressnigg N, Pöllabauer E-M, Aichinger G, et al. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. Lancet Infect Dis 2013; 13: 680–89.
Atazanavir-based therapy with pegylated interferon and ribavirin for patients with hepatitis C and HIV Mark Sulkowski and colleagues 1 assessed the safety and efficacy of boceprevir in combination with pegylated interferon alfa-2b (peginterferon) and ribavirin in patients with previously untreated HIV and hepatitis C virus (HCV) genotype 1. The authors showed that adding boceprevir to peginterferon–ribavirin significantly increased the probability of a sustained virological response 13
Correspondence
100
p=0·06
Percentage of patients achieving SVR
80
p=0·0042 60
p=0·052 40
20
0
29
49 Global
55
12
17 IL28B-CC
21
17
32
34
Il28B non-CC
Figure: Sustained virological response rate according to antiretroviral therapy (atazanavir boosted with ritonavir [blue], lopinavir boosted with ritonavir [red], and efavirenz [green]) in patients with HCV genotype 1 and HIV receiving their first pegylated interferon–ribavirin treatment Analysis was done on the whole population and according to IL28B genotype (rs129679860) using χ2 or Fisher´s tests.
(SVR) compared with peginterferon– ribavirin alone.1 In a subanalysis of this trial, we noted that when patients included in the peginterferon–ribavirin control arm were grouped according to antiretroviral regimen, those receiving atazanavir with ritonavir had higher SVR rates than those receiving any another antiretroviral regimen (69% [nine of 13] vs 4·7% [one of 21]; p
