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Papers of the Month – 2011
December, 2011
Nature Medicine, Vol. 17, No. 12, 1602-1609
AUTHORS
Fikri Y Avci, Xiangming Li, Moriya Tsuji & Dennis L Kasper
ABSTRACT
Glycoconjugate vaccines have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. To identify new approaches to enhancing glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. We found that in antigen-presenting cells a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein–derived peptide, this carbohydrate epitope binds major histocompatibility class II (MHCII) and stimulates carbohydrate- specific CD4+ T cell clones to produce interleukins 2 and 4—cytokines essential for providing T cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine that we constructed to maximize the presentation of carbohydrate-specific T cell epitopes is 50–100 times more potent and substantially more protective in a neonatal mouse model of group B Streptococcus infection than a vaccine constructed by methods currently used by the vaccine industry. Our discovery of how glycoconjugates are processed resulting in presentation of carbohydrate epitopes that stimulate CD4+ T cells has key implications for glycoconjugate vaccine design that could result in greatly enhanced vaccine efficacy.
Also see a related N&V article:
A sweet T cell response
Rino Rappuoli & Ennio De Gregorio
Nature Medicine, Vol. 17, No. 12, 1551-1552
Although protein-polysaccharide conjugate vaccines provide notable clinical benefits, it is still not fully understood how they work. A new mechanism of action for these vaccines has been identified in which T cells can recognize sugar epitopes in the context of the major histocompatibility complex (MHC) provided they are bound to a protein ‘anchor’, which allows binding of the sugar epitope to the MHC~
November, 2011
N Engl J Med 2011; 365:1863-75
AUTHORS
The RTS,S Clinical Trials Partnership
ABSTRACT
An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries.
From March 2009 through January 2011, we enrolled 15,460 children in two age categories — 6 to 12 weeks of age and 5 to 17 months of age — for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories.
In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.)
October, 2011
J. Exp. Med. Vol. 208 No. 11, 2217-2223
AUTHORS
Laszlo Kari, William M. Whitmire, Norma Olivares-Zavaleta, Morgan M. Goheen, Lacey D. Taylor, John H. Carlson, Gail L. Sturdevant, Chunxue Lu, Lauren E. Bakios, Linnell B. Randall,Michael J. Parnell, Guangming Zhong, and Harlan D. Caldwell
ABSTRACT
Blinding trachoma is an ancient neglected tropical disease caused by Chlamydia trachomatis for which a vaccine is needed. We describe a live-attenuated vaccine that is safe and efficacious in preventing trachoma in nonhuman primates, a model with excellent predictive value for humans. Cynomolgus macaques infected ocularly with a trachoma strain deficient for the 7.5-kb conserved plasmid presented with short-lived infections that resolved spontaneously without ocular pathology. Multiple infections with the attenuated plasmid-deficient strain produced no inflammatory ocular pathology but induced an anti-chlamydial immune response. Macaques vaccinated with the attenuated strain were either solidly or partially protected after challenge with virulent plasmid-bearing organisms. Partially protected macaques shed markedly less infectious organisms than controls. Immune correlates of protective immunity were not identified, but we did detect a correlation between MHC class II alleles and solid versus partial protection. Epidemiological models of trachoma control indicate that a vaccine with this degree of efficacy would significantly reduce the prevalence of infection and rates of reinfection, known risk factors which drive blinding disease.
September, 2011
DOI:10.1016/S1473-3099(11)70240-7
AUTHORS
Julie E Ledgerwood*, Chih-Jen Wei*, Zonghui Hu, Ingelise J Gordon, Mary E Enama, Cynthia S Hendel, Patrick M McTamney, Melissa B Pearce, Hadi M Yassine, Jeffrey C Boyington, Robert Bailer, Terrence M Tumpey, Richard A Koup, John R Mascola, Gary J Nabel, Barney S Graham, and the VRC 306 Study Team
ABSTRACT
Background: Because the general population is largely naive to H5N1 influenza, antibodies generated to H5 allow analysis of novel influenza vaccines independent of background immunity from previous infection. We assessed the safety and immunogenicity of DNA encoding H5 as a priming vaccine to improve antibody responses to inactivated influenza vaccination.
Methods: In VRC 306 and VRC 310, two sequentially enrolled phase 1, open-label, randomised clinical trials, healthy adults (age 18–60 years) were randomly assigned to receive intramuscular H5 DNA (4 mg) at day 0 or twice, at day 0 and week 4, followed by H5N1 monovalent inactivated vaccine (MIV; 90 μg) at 4 or 24 weeks, and compared with a two dose regimen of H5N1 MIV with either a 4 or 24 week interval. Antibody responses were assessed by haemagglutination inhibition (HAI), ELISA, neutralisation (ID80), and immunoassays for stem- directed antibodies. T cell responses were assessed by intracellular cytokine staining. After enrolment, investigators and individuals were not masked to group assignment. VRC 306 and VRC 310 are registered with ClinicalTrials.gov, numbers NCT00776711 and NCT01086657, respectively.
Findings In VRC 306, 60 individuals were randomly assigned to the four groups (15 in each) and 59 received the vaccinations. In VRC 310, of the 21 individuals enrolled, 20 received the vaccinations (nine received a two-dose regimen of H5N1 MIV and 11 received H5 DNA at day 0 followed by H5N1 MIV at week 24). H5 DNA priming was safe and enhanced H5-specific antibody titres following an H5N1 MIV boost, especially when the interval between DNA prime and MIV boost was extended to 24 weeks. In the two studies, DNA priming with a 24-week MIV boost interval induced protective HAI titres in 21 (81%) of 26 of individuals, with an increase in geometric mean titre (GMT) of more than four times that of individuals given the MIV-MIV regimen at 4 or 24 weeks (GMT 103–206 vs GMT 27–33). Additionally, neutralising antibodies directed to the conserved stem region of H5 were induced by this prime-boost regimen in several individuals. No vaccine-related serious adverse events were recorded.Interpretation DNA priming 24 weeks in advance of influenza vaccine boosting increased the magnitude of protective antibody responses (HAI) and in some cases induced haemagglutinin- stem-specific neutralising antibodies. A DNAMIV vaccine regimen could enhance the efficacy of H5 or other influenza vaccines and shows that anti-stem antibodies can be elicited by vaccination in man.
Also see a related commentary:Two is better than oneShan LuPublished Online October 4, 2011
DOI:10.1016/S1473- 3099(11)70256-0
In The Lancet Infectious Diseases, Julie Ledgerwood and colleagues reported on results from a phase 1 clinical trial showing that initial immunisation of individuals with a DNA vaccine expressing the haemagglutinin antigen of an avian source H5 subtype infl uenza virus, greatly improved the protective antibody responses elicited by a subsequent immunisation with the conventional inactivated influenza vacc
ine. By contrast, administration of two doses of the same inactivated influenza vaccine had much lower antibody responses than did the vaccine preceded by the DNA prime. Therefore, unmatched (heterologous
) prime-boost was more effective than matched (homologous) prime boost despite the same haemagglutinin antigen being used in both immunisation regimens, a finding gaining more attention lately.
Human beings are living under the threat of two types of influenza infections. One is seasonal influenza, which peaks in the winter seasons. Every year, the WHO issues guidelines on the selection of a formulation of a vaccine against seasonal influenza that covers the main circulating viruses during that period. The second type is pandemic influenza, which emerges suddenly and is transmitted quickly to a large proportion of the human population worldwide. Healthy people develop various degrees of immunity against seasonal influenza because of repeated natural exposure and, in some groups of people, through annual immunisations.
By contrast, the main threat of pandemic influenza is that people do not have preexisting immunity to minimise the effect of infection in public health. Timely development of protective immunity in the community is important to prevent the spread of an outbreak of pandemic influenza. A vaccine against pandemic influenza requires two doses to be effective, whereas the annual influenza vaccination against seasonal influenza only requires one inoculation. This distinction is a direct result of the differences in pre-existing immunity between these two types of influenza infections. Additionally, either higher dosing or the inclusion of an adjuvant is needed to achieve sufficient immunogenicity for vaccines against pandemic influenza that are currently available. Ledgerwood and colleagues validated a new strategy to improve the immunity of an influenza vaccine in naive human hosts, a strategy that had been reported in previous preclinical studies. Without changing the total number of immunisations, administration of a DNA vaccine is a more effective prime immunisationthan the inactivated influenza vaccine. This finding is especially important because a major limiting factor in the preparation against pandemic influenza is the restricted manufacturing capacity to produce enough doses of vaccines in a short period of time to cover the population in need.
If the vaccination strategy presented in this study was followed, the total amount of traditional vaccines against influenza would be reduced by half, which would allow more individuals to be vaccinated in a timely manner. The DNA vaccine is required as a second component with added complexity in this new prime-boost strategy. Although not shown in this report, preclinical studies have suggested that DNA primed antibody responses are usually long-lasting. Taking together, the report supports the idea of a prepandemic vaccination, since various DNA vaccines can easily be mixed together to provide broad coverage against several potential pandemic influenza viruses (even across different subtypes), long before any outbreak. Hosts primed with DNA vaccines are very likely to have reduced morbidity and mortality, even without a boost. This strategy gives public health officials the means needed to decrease the demand of traditional vaccines at the time of an outbreak of pandemic influenza. Moreover, this study1 is a milestone for DNA vaccine development. When used alone in man, DNA vaccines have not been sufficiently immunogenic, even with the use of various molecular adjuvants. By contrast, DNA vaccination is very effective in priming the human immune system to amplify the immune response when followed by a boost vaccination with either protein or viral vector vaccines. Ledgerwood and colleagues went further to show that DNA priming could be more effective than a type of influenza vaccine that has been licensed for human use. More studies are needed to see if doses of DNA and inactivated influenza vaccine can be reduced when such a heterologous prime-boost approach is used. It will also be interesting to compare the present approach with inactivated vaccines formulated with various adjuvants, particular results on the longevity of any recorded protective antibody responses. The results from the present study show that a long resting period between the prime and the boost is needed to achieve high protective antibody responses. Although the resting period between vaccinations is well known to be important in traditional vaccinology, such effect was remarkably clear in the present study.
This setting will offer a unique model to further dissect the mechanisms behind this phenomenon. By sequentially reducing the time between the prime and boost immunisations, it might be possible to determine whether antibody affinity maturation is implicated if the sequential sequence changes of immunoglobulin genes of protective antibodies are monitored. A well designed clinical study not only answers the clinical question at hand but also provides great insight to human biology. By using two vaccine components instead of one, Ledgerwood and colleagues certainly stimulated our thoughts more than the authors would have initially hoped.
August, 2011
N Engl J Med. 2011 Jun 16;364(24):2316-23
AUTHORS
DeVries AS, Harper J, Murray A, Lexau C, Bahta L, Christensen J, Cebelinski E, Fuller S, Kline S, Wallace GS, Shaw JH, Burns CC, Lynfield R.
ABSTRACT
A 44-year-old woman with long-standing common variable immunodeficiency who was receiving intravenous immune globulin suddenly had paralysis of all four limbs and the respiratory muscles, resulting in death. Type 2 vaccine-derived poliovirus was isolated from stool. The viral capsid protein VP1 region had diverged from the vaccine strain at 12.3% of nucleotide positions, and the two attenuating substitutions had reverted to the wild-type sequence. Infection probably occurred 11.9 years earlier (95% confidence interval [CI], 10.9 to 13.2), when her child received the oral poliovirus vaccine. No secondary cases were identified among close contacts or 2038 screened health care workers. Patients with common variable immunodeficiency can be chronically infected with poliovirus, and poliomyelitis can develop despite treatment with intravenous immune globulin.
July, 2011
N Engl J Med. 2011 Jun 16;364(24):2283-92
AUTHORS
Patel MM, López-Collada VR, Bulhões MM, De Oliveira LH, Bautista Márquez A, Flannery B, Esparza-Aguilar M, Montenegro Renoiner EI, Luna-Cruz ME, Sato HK, Hernández-Hernández Ldel C, Toledo-Cortina G, Cerón-Rodríguez M, Osnaya-Romero N, Martínez-Alcazar M, Aguinaga-Villasenor RG, Plascencia-Hernández A, Fojaco-González F, Hernández-Peredo Rezk G, Gutierrez-Ramírez SF, Dorame-Castillo R, Tinajero-Pizano R, Mercado-Villegas B, Barbosa MR, Maluf EM, Ferreira LB, de Carvalho FM, dos Santos AR, Cesar ED, de Oliveira ME, Silva CL, de Los Angeles Cortes M, Ruiz Matus C, Tate J, Gargiullo P, Parashar UD
ABSTRACT
Backgroud: Because postlicensure surveillance determined that a previous rotavirus vaccine, RotaShield, caused intussusception in 1 of every 10,000 recipients, we assessed the association of the new monovalent rotavirus vaccine (RV1) with intussusception after routine immunization of infants in Mexico and Brazil.
Methods: We used case-series and case-control methods to assess the association between RV1 and intussusception. Infants with intussusception were identified through active surveillance at 69 hospitals (16 in Mexico and 53 in Brazil), and age-matched infants from the same neighborhood were enrolled as controls. Vaccination dates were verified by a review of vaccination cards or clinic records.
Results: We enrolled 615 case patients (285 in Mexico and 330 in Brazil) and 2050 controls. An increased risk of intussusception 1 to 7 days after the first dose of RV1 was identified among infants in Mexico with the use of both the case-series method (incidence ratio, 5.3; 95% confidence interval [CI], 3.0 to 9.3) and the case-control method (odds ratio, 5.8; 95% CI, 2.6 to 13.0). No significant risk was found after the first dose among infants in Brazil, but an increased risk, albeit smaller than that seen after the first dose in Mexico–an increase by a factor of 1.9 to 2.6 – was seen 1 to 7 days after the second dose. A combined annual excess of 96 cases of intussusception in Mexico (approximately 1 per 51,000 infants) and in Brazil (approximately 1 per 68,000 infants) and of 5 deaths due to intussusception was attributable to RV1. However, RV1 prevented approximately 80,000 hospitalizations and 1300 deaths from diarrhea each year in these two countries.
Conclusions: RV1 was associated with a short-term risk of intussusception in approximately 1 of every 51,000 to 68,000 vaccinated infants. The absolute number of deaths and hospitalizations averted because of vaccination far exceeded the number of intussusception cases that may have been associated with vaccination.
June, 2011
Nature 2011 May 26; 473:523–527
AUTHORS
Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, Whizin N, Oswald K, Shoemaker R, Swanson T, Legasse AW, Chiuchiolo MJ, Parks CL, Axthelm MK, Nelson JA, Jarvis MA, Piatak M Jr, Lifson JD, Picker LJ
ABSTRACT
The acquired immunodeficiency syndrome (AIDS)-causing lentiviruses human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) effectively evade host immunity and, once established, infections with these viruses are only rarely controlled by immunological mechanisms. However, the initial establishment of infection in the first few days after mucosal exposure, before viral dissemination and massive replication, may be more vulnerable to immune control. Here we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors establish indefinitely persistent, high-frequency, SIV-specific effector memory T-cell (TEM) responses at potential sites of SIV replication in rhesus macaques and stringently control highly pathogenic SIVMAC239 infection early after mucosal challenge. Thirteen of twenty-four rhesus macaques receiving either RhCMV vectors alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors (versus 0 of 9 DNA/Ad5-vaccinated rhesus macaques) manifested early complete control of SIV (undetectable plasma virus), and in twelve of these thirteen animals we observed long-term (?1 year) protection. This was characterized by: occasional blips of plasma viraemia that ultimately waned; predominantly undetectable cell- associated viral load in blood and lymph node mononuclear cells; no depletion of effector-site CD4+ memory T cells; no induction or boosting of SIV Env-specific antibodies; and induction and then loss of T-cell responses to an SIV protein (Vif) not included in the RhCMV vectors. Protection correlated with the magnitude of the peak SIV-specific CD8+ T-cell responses in the vaccine phase, and occurred without anamnestic T-cell responses. Remarkably, long- term RhCMV vector-associated SIV control was insensitive to either CD8+ or CD4+ lymphocyte depletion and, at necropsy, cell-associated SIV was only occasionally measurable at the limit of detection with ultrasensitive assays, observations that indicate the possibility of eventual viral clearance. Thus, persistent vectors such as CMV and their associated TEM responses might significantly contribute to an efficacious HIV/AIDS vaccine.
May, 2011
Nature 2011 Feb 24;470:543-547
AUTHORS
Kasturi SP, Skountzou I, Albrecht RA, Koutsonanos D, Hua T, Nakaya HI, Ravindran R, Stewart S, Alam M, Kwissa M, Villinger F, Murthy N, Steel J, Jacob J, Hogan RJ, García-Sastre A, Compans R, Pulendran B
ABSTRACT
Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.
April, 2011
New Engl J Med 2011; 364:1326-33
AUTHORS
Monath TP, Fowler E, Johnson CT, Balser J, Merribeth J, Morin MJ, Sisti M, Trent DW
ABSTRACT
Yellow fever is a lethal, flavivirus disease carried by mosquitoes. The only currently available vaccine is a live attenuated virus (17D) developed in 1936 and widely used to protect travelers to and residents of endemic areas in tropical South America and Africa. Although remarkably immunogenic, the 17D vaccine may cause serious viscerotropic and neurotropic adverse events and anaphylaxis. Viscerotropic disease is a life-threatening active infection of the liver and visceral organs with 17D virus resembling naturally-acquired yellow fever. Neurotropic disease typically follows invasion of the brain by the live, replicating vaccine virus. Fortunately these adverse events are rare, but the lethality of viscerotropic adverse events (63%) is unprecedented for any vaccine. Recently Hayes drew attention to the need for a safer yellow fever vaccine (Vaccine 2010; 28:8073-6). In the current paper, the authors describe the first clinical trial of an inactivated yellow fever vaccine produced in cell cultures and adsorbed to alum adjuvant. Strong neutralizing antibody responses (the mediator of protection against yellow fever) were observed in all subjects who received two doses (21 days apart) of 4.8 micrograms of antigen, a dose similar to that contained in commercial vaccines against related viruses, such as Japanese encephalitis. Safety and tolerability of the vaccine appeared to be good. Although two inoculations of vaccine were required (compared to a single dose of the live vaccine), the new non-replicating vaccine may potentially have advantages in safety and could be used in persons with precautions and contraindications to 17D. The reported study is the first step in product development that will require additional clinical trials demonstrating safety and immunogenicity required for regulatory approval.
March, 2011
Proceedings of the National Academy of Sciences of the United States of America, 2011 Apr 5; 108(14):5730-5
AUTHORS
Kerry A. Millington, Sarah M. Fortune, Jeffrey Low, Alejandra Garces, Suzanne M. Hingley- Wilson, Melissa Wickremasinghe, Onn M. Kon, and Ajit Lalvania
ABSTRACT
The 6-kDa early secretory antigenic target of Mycobacterium tuberculosis (ESAT-6) and the 10- kDa culture filtrate antigen (CFP-10), encoded in region of difference 1 (RD1) and secreted by the ESAT-6 system 1 (Esx-1) secretion system, are the most immunodominant and highly M. tuberculosis (MTB)-specific antigens. These attributes are responsible for their primary importance in tuberculosis (TB) immunodiagnosis and vaccine development. Rv3615c [Esx-1 substrate protein C (EspC)], encoded outside RD1, is similar in size and sequence homology to CFP-10 and ESAT-6, suggesting it might be a target of cellular immunity in TB. Using ex vivo enzyme-linked immunospot- and flow cytometry-based cytokine-secretion assay, we comprehensively assessed cellular immune responses to EspC in patients with active TB, latently infected persons, and uninfected bacillus Calmette-Guerin (BCG)-vaccinated controls. EspC was at least as immunodominant as ESAT-6 and CFP-10 in both active and latent TB infection. EspC contained broadly recognized CD4(+) and CD8(+) epitopes, inducing a predominantly CD4(+) T-cell response that comprised functional T-cell subsets secreting both IFN-gamma and IL-2 as well as functional T-cell subsets secreting only IFN-gamma. Surprisingly, T-cell responses to EspC were as highly specific (93%) for MTB infection as responses to ESAT-6 and CFP-10, with only 2 of 27 BCG-vaccinated controls responding to each antigen. Using quantitative proteomics and metabolically labeled mutant and genetically complemented MTB strains, we identified the mechanism of the specificity of anti-EspC immunity as the Esx-1 dependence of EspC secretion. The high immunodominance of EspC, equivalent to that of ESAT-6 and CFP-10, makes it a TB vaccine candidate, and its high specificity confers strong potential for T-cell-based immunodiagnosis.
February, 2011
The New England Journal of Medicine, Feb 3, 2011, 364(5):401-411
AUTHORS
Anna R. Giuliano, Joel M. Palefsky, Stephen Goldstone, Edson D. Moreira, Jr., Mary E. Penny, Carlos Aranda, Eftyhia Vardas, Harald Moi, Heiko Jessen, Richard Hillman, Yen-Hwa Chang, Daron Ferris, Danielle Rouleau, Janine Bryan, J. Brooke Marshall, Scott Vuocolo, Eliav Barr, David Radley, Richard M. Haupt and Dalya Guris
Related “Perspective” from Dr. Jane J. Kim
Weighing the benefits and costs of HPV vaccination of young men
The New England Journal of Medicine, Feb. 3, 2011, 364(5):393-395
ABSTRACT
Though the evidence regarding the efficacy of the HPV vaccines to this point has centered on the prevention of HPV infection and diseases in girls and women, the data presented by Giuliano et al. in this issue of the Journal (pages 401–411) affirm the potential for HPV vaccines to prevent related disease in boys and men. The investigators report the efficacy of the quadrivalent HPV vaccine in preventing infections with the HPV types included in the vaccine, as well as external genital lesions, primarily genital warts, in young men 16 to 26 years of age.”
These data informed the 2009 approval by the Food and Drug Administration (FDA) of the quadrivalent HPV vaccine for the prevention of genital warts in young men in the United States and the subsequent recommendation from the Advisory Committee on Immunization Practices (ACIP), which advises the Centers for Disease Control and Prevention (CDC), for the permissive use of the vaccine in boys and young men 9 to 26 years of age. The ACIP stopped short of supporting routine HPV vaccination of adolescent boys, even though routine vaccination of girls between the ages of 11 and 12 years (and as early as 9 years) has been recommended since 2007. However, the committee did recommend financial coverage by the CDC Vaccines for Children program for eligible boys 18 years of age or younger. Since these decisions were made, newer data have shown that the quadrivalent HPV vaccine is effective in preventing anal intraepithelial neoplasia, a precursor to anal cancer, in men, particularly in men who have sex with men. Q, the basis of this new evidence, the FDA recently approved the expanded use of the quadrivalent vaccine to include the prevention of anal lesions and cancer in people of both sexes, a decision that has reignited the debate over routine HPV vaccination of young men.”
The report by Giuliano et al. undoubtedly gives us cause to celebrate the extraordinary potential for HPV vaccination to improve health in both women and men. And although enthusiasm for universal vaccination may initially be tempered by uncertainties about the vaccine’s safety, efficacy, and duration of protection (as well as its uptake, acceptability, and cost), many of these factors could very well change in the future. For example, the cost effectiveness profile of routine vaccination of young men will improve if the evidence of efficacy continues to mount, the vaccine price declines, or coverage among girls and women remains low.
January, 2011
Vaccine, 29(5):873-7
AUTHORS
Rao M, Peachman KK, Li Q, Matyas GR, Shivachandra SB, Borschel R, Morthole VI, Fernandez-Prada C, Alving CR, Rao VB
ABSTRACT
One of the most difficult challenges in vaccine development is the process of adjuvant selection. In addition to potency, the adjuvant must be safe, optimize the immune response, contain easily available materials, and be relatively inexpensive and easy to manufacture. One approach in the past has been to compare multiple adjuvant systems for safety and potency in small animal models but their predictive value is often poor and might even conflict with data from human trials. In this study we examined a new algorithm in which seven adjuvant systems were compared for efficacy and potency using a single antigen, the protective antigen from Bacillus anthracis, in nonhuman primates (NHPs). We selected the formulations that are generic, easy to manufacture, likely to be safe, and might be useful for development of vaccines against difficult, neglected, or infrequent diseases. We found that the most successful adjuvant systems were those that included liposomes containing generic monophosphoryl lipid A (MPLA). In fact, the formulation that elicited the highest antigen-specific and lethal toxin neutralizing titers reported to date was the one in which liposomes containing generic MPLA were simply mixed with the antigen. This study shows that the NHP model is attractive as a primary alternative to small animal models to select new and superior adjuvants and that the generic liposomal MPLA adjuvant system might be safely and easily employed with numerous human vaccine formulations.
