The New H1N1 and HPV Vaccines and Old Fears Ari Balofskya, Nancy Agmon-Levina and Yehuda Shoenfelda,B

CE: Namrta; BOR/543; Total nos of Pages: 6; BOR 543

The new H1N1 and HPV vaccines and old fears Ari Balofskya, Nancy Agmon-Levina and Yehuda Shoenfelda,b

aThe Zabludowicz Center for Autoimmune Diseases Purpose of review and Department of Medicine B, Sheba Medical Center, Tel Hashomer and bIncumbent of the Laura Schwarz- Vaccines remain an effective yet controversial method for preventing infectious Kip Chair for Research of Autoimmune Diseases, diseases like those caused by human papillomavirus (HPV) and pandemic influenza Tel-Aviv University, Tel Aviv, Israel (H1N1). However, reports of postvaccination serious adverse events such as Correspondence to Yehuda Shoenfeld, MD, FRCP, autoimmunity, although rare, have caused great concerns among the general public. We The Zabludowicz Center for Autoimmune Diseases, Department of Medicine ‘B’, The Chaim Sheba Medical aimed to summarize the recent knowledge regarding such interactions, mainly focusing Center, Tel-Hashomer 52621, Israel on these new vaccines. Tel: +972 3 5302652; fax: +972 3 5352855; e-mail: [email protected] Recent findings Autoimmune phenomena have been associated with specific vaccines, and Current Opinion in Rheumatology 2010, 22:000–000 mechanisms for how this occurs have been elucidated for different vaccine components like the infectious antigen and adjuvant. New vaccines that include infrequently used or new adjuvants have been introduced for both HPV and the H1N1-pandemic influenza. Additionally, two formulations have been approved for use against HPV, and various formulations for the H1N1 influenza vaccine. Whereas preliminary studies are successful, early and late postimmunization events and differences between reagents must be followed closely, especially during mass immunization programs. Summary As more diseases are found to be preventable through vaccination, it is of great importance to design better, more effective and better tolerated vaccines. This goal may be achieved utilizing improved vaccine components and a postmarketing system that may allow detection of rare postvaccination phenomena.

Keywords adjuvant, autoimmunity, H1N1 inﬂuenza vaccine, human papilloma virus, vaccine

Curr Opin Rheumatol 22:000–000 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8711

tered concerns have erupted into a widespread protest Introduction regarding the efficacy and safety of such vaccines, as well The development of vaccination has proven itself to be a as the economic impact of decisions regarding vaccine tremendously successful and cost-effective asset for pre- production and distribution. This debate surrounding ventive medicine. Vaccines have the ability to prevent vaccines has resulted in decreased compliance to their acute and chronic infectious diseases, and even eradicate use, and thus a decrease in their herd evaluated efficacy. some infectious diseases such as smallpox and polio Therefore, we aim in this review to summarize the [1,2]. New advances and improvements in vaccines relationship between vaccination and autoimmunity, are increasingly important, especially now in the era of focusing on the new 2009 H1N1 swine flu and HPV the swine flu pandemic [3], and with the prospect of vaccines. vaccinating against malignancies like cervical cancer [4]. Following the approval of these new and undeniably needed vaccines, a growing concern has been raised Vaccines associated with autoimmunity regarding their safety for the general population as well There are adverse reactions to vaccines, as with any other as for specific groups (i.e. pregnant women, infants, drug, but vaccines unlike drugs are usually intended for patients with autoimmune diseases, etc.). The pro- the healthy population, and thus their adverse events are duction of several vaccines targeted against a single less well tolerated [6]. Most adverse events associated infectious agent, such as adjuvanted and nonadjuvanted with vaccination are mild and self-limiting, whereas more anti-H1N1 vaccines, or vaccines directed against the rare severe reactions include hypersensitivity, induction human papillomavirus (HPV), of which one contains of the actual infection, or autoimmune phenomena. two adjuvants, have raised even more questions and There are many case reports, case series and studies debate surrounding their use [5]. Recently, these scat- describing autoantibody induction, the development of

1040-8711 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/BOR.0b013e32833a43c3 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE: Namrta; BOR/543; Total nos of Pages: 6; BOR 543

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autoimmune phenomena and overt autoimmune disease or recombinant antigens were also associated with auto- following vaccination [7]. The most frequently reported immunity. The most probable mechanism by which this are arthritis, neuropathy, encephalitis, vasculitis, and occurs is molecular mimicry between the infectious anti- demyelination. These manifestations are rare, can be gen and self-antigens, as well as other mechanisms like nonspecific, may occur late, and are very often not epitope spreading, bystander activation and polyclonal reported. As such, it is difficult to define a causal relation- activations [7]. ship between these autoimmune phenomena and prior vaccination. Nevertheless, some vaccines have been Adjuvants are used in human and animal vaccines in accepted to play a causal role in the development of order to increase antigen recognition and desired immune autoimmunity, such as during the 1976 outbreak of response towards the infectious antigen. They also ‘swine flu’. A causal relationship was noted between enable the decrement of antigen amount and thereby Guillain-Barre´ syndrome (GBS) and anti-swine flu the production of a larger amount of vaccines, which are vaccine. This is especially relevant given the current clearly needed during a pandemic such as H1N1 [14]. 2009 H1N1 pandemic [8], and is discussed further below. Adjuvants enhance the immune response via their abil- Potential causal relationships have been also implicated for ities to mimic conserved antigens, interact with Toll-like oral polio vaccine and transverse myelitis, diphtheria- receptors (TLRs), and activate macrophages, dendritic tetanus-pertussis (DTP) and measles-mumps-rubella cells, and lymphocytes [12,15]. Adjuvants further aid (MMR) combinations and arthritis, and MMR and auto- in the translocation of antigens to lymph nodes, inducing immune thrombocytopenia. Other associations were cytokine release, preventing antigen destruction, and suggested such as GBS following Menactra meningococcal may conserve vaccine efficacy even if antigenic drift vaccination (MCV4), type I diabetes after hemophilus has occurred [16]. Previously, aluminum adjuvants were influenza B vaccination, and multiple sclerosis (MS) and added to most human vaccines, but in the hope of transverse myelitis following HBV vaccination [7,9]. producing better tolerated and more effective vaccines, Additionally, we have to appreciate the latency period newer adjuvants have been developed. A virus-like that exists between vaccination and adverse events. Some particle adjuvant, called virosome, was developed and autoimmune diseases may occur shortly after a triggering utilized efficaciously in the seasonal influenza vaccine infection, such as rheumatic fever following streptococcal [17–19]. Oil-based adjuvants such as AS03 and MF59 infection, whereas others may only arise much later. This have also been included in the arsenal of human adju- same concept applied to autoimmune phenomena follow- vants. MF59, composed of squalene, polyoxyethylene ing vaccination indicates that they may occur either within sorbitan monooleate and sorbitan trioleate, and AS03 days or much after the vaccine was administered. The were recently included in the pandemic H1N1 influenza requirement of several doses for vaccination extends the vaccines, and are both considered to have a good safety time period in which adverse events may occur, and several profile [12,20,21,22,23]. Other recently introduced events have been reported years postvaccination. For adjuvants that work through TLR signaling include the instance, possible demyelination in childhood was recently IC31 for influenza vaccine, and AS04 for the bivalent associated with HBV immunization administered 3 years vaccine against HPV [24,25,26]. Whereas these com- prior [10]. Consequently, the concept of temporal associ- ponents are extremely useful for enhancing the effects of ation must be kept in mind when relating new auto- a vaccine, they come with risks. Different adjuvants (i.e. immune events to prior vaccinations. silicon) may induce by themselves an autoimmune condition termed ‘the adjuvant diseases’ [27], of which macrophagic myofasciitis (MMF) is perhaps the best Mechanisms of autoimmunity defined. This is a rare condition that may appear months The development of autoimmunity requires both genetic and even years following immunization, and is manifest propensity and exposure to environmental factors that act by chronic fatigue, myalgias, and the development of as triggers of diseases. Whereas this most commonly takes autoimmune phenomena in about a third of patients place in the form of exposure to infectious agents, [12,28]. MMF is considered to possibly be the result vaccines may induce an autoimmune response in a similar of aluminum adjuvant remaining for years at the site of manner [7,11,12,13]. Vaccines are constructed of inoculation. The rarity of this postimmunization event infectious antigens, adjuvants and other ingredients, of may be explained by the observations that alum probably which the former may lead to autoimmunity. triggers MMF only in genetically susceptible patients carrying the HLA–DRB1Ã01. Another group of adju- Infectious antigens derived from bacteria and viruses, as vants, the mineral oils (i.e. pristane, squalene), were also well as those utilized for the production of live attenuated associated with adverse events such as the induction of vaccines such as MMR and oral polio vaccine (OPV), sclerosing lipomas, plasmacytomas, systemic lupus have been linked to the induction of a self-reactive erythematosus (SLE)-like disease and arthritis in geneti- immune response [7,9]. In recent years, inactivated cally susceptible animal models [29]. Of note in the Gulf

The new H1N1 and HPV vaccines and old fears Balofsky et al. 3

War syndrome that shares many similarities with MMF, Their advantage over unadjuvanted vaccine is yet to be an association with squalene was suggested, as serum determined [14]. antibodies to squalene were found in most symptomatic patients [30] in one study, whereas no association was reported in another [31]. The human papillomavirus vaccine Cervical cancer is a devastating malignancy affecting Thus, although adjuvants are beneficial in improving women worldwide, inflicted in many cases by the HPV. vaccine immunogenicity, their ability to induce harm Therefore, the introduction of vaccines against HPV has on rare occasions has also been observed. provided a novel approach in the fight against cervical and other cancers, although the long-term effects on morbidity and mortality require further studies. Systematic review of Influenza and H1N1 six clinical trials showed the HPV vaccines reduce lesions With the advent of the new H1N1 influenza pandemic, it with 93% efficacy in the cervix, vulva, vagina, and ano- has become a priority to develop a well tolerated and genital region [50]. Two forms of the vaccine exist: the effective vaccine for prevention of the ‘swine flu’. How- quadrivalent Gardasil (MSD), which induces immune ever, a notable increase in GBS was documented follow- response against four strains of the virus (HPV 6, 11, 16, ing swine influenza vaccination in 1976–1977, causing 18), and the bivalent Cervarix (GSK) directed at HPV 16 concern about the current vaccine [32,33]. Furthermore, and 18 [51,52]. Both are composed of HPV L1 proteins the vaccine component responsible for this association that self-assemble to form virus-like particles, but differ in was never ascertained, though Nachamkin et al. [34] the use of adjuvants. Gardasil uses aluminum hydroxypho- showed that influenza vaccines contain structures that are sphate sulfate, whereas Cervarix uses the oil-based adju- able to induce the anti-GM1 antibody via molecular vant AS04 composed of the TRL4 ligand monophosphoryl mimicry [35]. GM1 is an antigen located at the axo- lipid A (MPL), and aluminum hydroxide. This combi- lemma of motor nerves, and antibodies against it have nation represents a novel approach of using a double been shown to reduce depolarization-induced calcium adjuvanted system. Aluminum salts induce a Th2 immune influx, block muscle action potentials, and induce the response, whereas AS04 induces a mixed Th1/Th2 development of GBS [36–38,39]. response through interactions with TLRs. The combination of both was found to enhance humoral and memory All new H1N1 influenza vaccines are based around the B-cell immunity compared with aluminum alone. Unlike A/California/7/2009(H1N1)v strain, but differ in their use aluminum, AS04 is responsible for inducing cytokines and of adjuvants (i.e. aluminum phosphate, AS03 and MF59) NF-kB, as well as activation of dendritic cells and mono- [40], whereas the FDA-approved vaccines contain no cytes. Enhanced B-cell activation may occur due to an adjuvant [41]. The safety and immunogenicity of a increase in antigen presenting cell (APC)-mediated T-cell single unadjuvanted vaccine dose, administered to 240 activation, or as a result of the generation of high-affinity healthy adults, were found to be immunogenic and well Th cells in the draining lymph node. Both of these mech- tolerated by Greenberg et al. [42]. Similarly Zhu et al. [43] anisms, however, may be optimized by the aluminum assessed vaccines with and without alum, and found no component, which prolongs the cytokine response to serious adverse events in a short follow-up period apart AS04 [53]. The double adjuvanted HPV vaccine, from increased local reactions to the adjuvanted vaccine. although used only for several years, is considered to have The authors unexpectedly reported that unadjuvanted a good overall safety profile [26,54], and Verstraeten et al. vaccine was more effective in inducing immunity com- [55] showed through an integrated analysis of over 68 000 pared with the alum adjuvanted vaccine. Whereas emul- participants that use of AS04 in different vaccines does not sion adjuvants are relatively new, MF59 adjuvanted increase rates of autoimmune disorders. Similarly, the vaccines were associated with the same incidence of quadrivalent HPV vaccine Gardasil that has been used autoimmunity as vaccines without MF59 [44,45], and for a longer period of time is considered well tolerated. As it do not cause production of antisqualene antibodies [46]. is important to determine the safety profile of vaccines in On the contrary, Clark et al. [47] found that vaccine combination with other currently used vaccines, concomi- immunogenicity was not enhanced by the addition of the tant use of Gardasil and Repevax (diphtheria, pertussis, MF59 adjuvant, and although no serious adverse events tetanus, and poliomyelitis vaccine), as well as Gardasil and were reported, increased local pain was associated with hepatitis B vaccines was found to be well tolerated apart MF59. The AS03 adjuvanted vaccines have been given to from some increase in injection-site inflammation [56,57]. more than 39 000 individuals and seem to be well However, a longer follow-up period postquadrivalent HPV tolerated [48,49]. Currently, both oil-adjuvanted vaccination has considered an association with autoimmu- vaccines have been associated with local events in up nity, recognizing that the expected rate of such phenom- to 18% of patients: fever (1–2%), headaches (6–7%), ena in young girls should always be taken into account myalgia and arthralgia (8%), and rare allergic reactions. [58]. Through postlicensure surveillance of Gardasil

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[59], 60 studies of autoimmune disorders including SLE, as many adverse events have been associated with the rheumatoid arthritis, and mixed connective tissue disease administration of vaccine up to 3 years prior. Specific were documented, 51 of which were associated with manifestations should be scrutinized, such as throm- Gardasil alone. Additionally, a statistically significant boembolic events following HPV and neurological ones increased incidence of thromboembolic events was following H1N1 vaccinations. Host-susceptibility factors, observed. In another study, Sutton et al. [60] described especially pharmacogenomics, may shed more light on five patients exhibiting signs of demyelinating disorders these rare although severe adverse events. Consequently, within 21 days postvaccination with Gardasil. Since the our aim should be to produce the ideal well tolerated and risk of multiple sclerosis is intrinsically high in the popu- immunogenic vaccine, which may or may not contain lation being vaccinated with HPV, occurrence of MS in adjuvants, and can be administrated to healthy individ- those vaccinated must take into account the expected uals with minimal adverse events. frequency in comparable populations not receiving the vaccination. Acknowledgement Disclosure: Professor Yehuda Shoenfeld appeared in court on the With two vaccine formulations available for HPV, the issue of vaccine-induced autoimmune conditions. question of safety, efficacy, and which vaccine to choose comes to the forefront. As Gardasil has been licensed for use longer than Cervarix, there are more studies available References and recommended reading Papers of particular interest, published within the annual period of review, have on it to demonstrate its safety. But whereas Cervarix is been highlighted as: newer, it has been shown to have a favorable safety record of special interest of outstanding interest [61 ,62]. Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000). Einstein et al. [63 ] compared the safety and immuno- 1 Ravanfar P, Satyaprakash A, Creed R, Mendoza N. Existing antiviral vaccines. genicity of Cervarix and Gardasil. Cervarix was found to Dermatol Ther 2009; 22:110–128. This article discusses various diseases and the vaccines that have been developed induce higher levels of neutralizing antibody in serum for them. Topics including recommendations and efficacy provide the reader with a and cervicovaginal secretions, and of circulating antigen- good understanding of vaccination for the prevention of disease. specific memory B-cells and T-cells directed at HPV 16 2 Mendoza N, Ravanfar P, Satyaprakash A, et al. Existing antibacterial vaccines. and 18 strains compared with Gardasil. This may Dermatol Ther 2009; 22:129–142. 3 Scalera NM, Mossad SB. The first pandemic of the 21st century: a review of represent the advantage of using the double adjuvanted the 2009 pandemic variant influenza A (H1N1) virus. Postgrad Med 2009; system, although long-term studies are required to deter- 121:43–47. This article reviews the current information regarding the 2009 pandemic influenza, mine the significance of these differences in regard to and serves as important background information regarding safety and prevention. both efficacy and safety. Of note, Cervarix was associated 4 Albers AE, Kaufmann AM. Therapeutic human papillomavirus vaccination. with more injection site reactions, which may suggest a Public Health Genomics 2009; 12:331–342. This review describes the importance of vaccination in the prevention of cervical tendency of the vaccine components to remain at the site cancers, as well as current advances and difficulties that need to be overcome. of injection [53 ]. 5 Hutchinson DJ, Klein KC. Human papillomavirus disease and vaccines. Am J Health Syst Pharm 2008; 65:2105–2112. Taken all together, in order to make a definitive state- 6 Vaccines versus viruses [editorial]. Nat Med 2009; 15:119. ment on the superior efficacy and safety of HPV vaccines, 7 Agmon-Levin N, Paz Z, Israeli E, Shoenfeld Y. Vaccines and autoimmunity. Nat Rev Rheumatol 2009; 5:648–652. more studies and longer follow-up periods are required. This review describes in detail the connection between vaccination and the development of autoimmune phenomena, as well possible mechanisms for these events. This will prove important in understanding and preventing further occur- rences with the production of new vaccines. 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The implications of these findings are vaccines. A long-term follow-up seems to be needed, significant for producing better tolerated adjuvants with fewer adverse effects.

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Various topics, including formulation, safety, and immunogenicity, are This article discusses the development of GBS following swine influenza vaccine, mentioned in order to give the reader a comprehensive understanding of what and the importance in preventing it for the current swine flu vaccine. makes the vaccines different.

6 Infectious arthritis and immune dysfunction

52 Schiller JT, Castellsague´ X, Villa LL, et al. An update of prophylactic human 58 Callreús T, Svanstro¨ m H, Nielsen NM, et al. Human papillomavirus immunisa- papillomavirus L1 virus-like particle vaccine clinical trial results. Vaccine 2008; tion of adolescent girls and anticipated reporting of immune-mediated adverse 26 (Suppl 10):K53–K61. events. Vaccine 2009; 27:2954–2958. This study determined the incidence of immune-mediated disorders in the popula- 53 Didierlaurent AM, Morel S, Lockman L, et al. AS04, an aluminum salt- and tion expected to be vaccinated with HPV vaccine, as well as the rate at which these TLR4 agonist-based adjuvant system, induces a transient localized innate disorders will occur in relation to the vaccination schedule. immune response leading to enhanced adaptive immunity. J Immunol 2009; 59 Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for 183:6186–6197. quadrivalent human papillomavirus recombinant vaccine. J Am Med Assoc This study describes the mechanism and activity of the new AS04 adjuvant which 2009; 302:750–757. works by signaling through TLRs. Further discussion includes how the compo- This study details adverse events reported by passive surveillance since the nents interact in inducing a response. introduction of the quadrivalent HPV vaccine in 2006. It gives both a preliminary safety report on the vaccine, as well as information on what adverse events to be 54 Schwarz TF. AS04-adjuvanted human papillomavirus-16/18 vaccination: aware of in the future. recent advances in cervical cancer prevention. Expert Rev Vaccines 2008; 60 Sutton I, Lahoria R, Tan I, et al. CNS demyelination and quadrivalent HPV 7:1465–1473. vaccination. Mult Scler 2009; 15:116–119. 61 Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety 55 Verstraeten T, Descamps D, David MP, et al. Analysis of adverse events of profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 potential autoimmune aetiology in a large integrated safety database of AS04 virus-like particle vaccine. Pediatr Infect Dis J 2009 [Epub ahead of print]. adjuvanted vaccines. Vaccine 2008; 26:6630–6638. This study reviews the current data regarding adverse events following HPV This study investigates reports of possible autoimmune phenomena following use of AS04 adjuvanted vaccines, especially relevant for its use in the bivalent HPV immunization by examining recent clinical trials and passive surveillance. vaccine. 62 van der Maas NA, Kemmeren JM, de Melker HE. Safety of the bivalent human papillomavirus vaccine: results following administration of more than 192,000 56 Vesikari T, Van Damme P, Lindblad N, et al. An open-label, randomized, doses. Ned Tijdschr Geneeskd 2009; 153:A964. multicenter study of the safety, tolerability, and immunogenicity of quad- 63 Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and rivalent human papillomavirus (types 6/11/16/18) vaccine given concomi- safety of Cervarix() and Gardasil((R)) human papillomavirus (HPV) cervical tantly with diphtheria, tetanus, pertussis, and poliomyelitis vaccine in healthy cancer vaccines in healthy women aged 18–45 years. Hum Vaccin 2009; adolescents 11 to 17 years of age. Pediatr Infect Dis J 2009 [Epub ahead of 5:705–719. print]. This study compares safety and immunogenicity in women following vaccination This study investigated the safety and efficacy of inoculation with multiple vaccines with the two HPV vaccines. The implications of these results are important in alongside the quadrivalent HPV vaccine. This is especially important due to the determining which vaccine is most appropriate for use. recommendations for and widespread use of the HPV vaccine. 64 Klein NP, Ray P, Carpenter D, et al. Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies. Vaccine 2009 57 Wheeler CM, Bautista OM, Tomassini JE, et al. Safety and immunogenicity of [Epub ahead of print]. co-administered quadrivalent human papillomavirus (HPV)-6/11/16/18 L1 virus-like particle (VLP) and hepatitis B (HBV) vaccines. Vaccine 2008; 65 Stewart AM. Mandatory vaccination of healthcare workers. N Engl J Med 26:686–696. 2009; 361:2015–2017.