Historical review of clinical vaccine studies at Oswaldo Cruz Institute and Oswaldo Cruz Foundation - technological development issues

Martins, Reinaldo de Menezes; Possas, Cristina de Albuquerque; Homma, Akira

doi:10.1590/0074-02760140346

Reinaldo de Menezes Martins

Conselho Político e Estratégico, Bio-Manguinhos-Fiocruz, Rio de Janeiro, RJ, Brasil

Cristina de Albuquerque Possas

Conselho Político e Estratégico, Bio-Manguinhos-Fiocruz, Rio de Janeiro, RJ, Brasil

Akira Homma

Conselho Político e Estratégico, Bio-Manguinhos-Fiocruz, Rio de Janeiro, RJ, Brasil

+ Corresponding author: rmenezes@bio.fiocruz.br

Reference	Rationale of the investigation	Comments
Soper and Smith (1938)Soper FL, Smith HH 1938. Yellow fever vaccination with cultivated virus and immune and hyperimmune serum. Am J Trop Med Hyg 18: 111-134.	Use of substrain 17E in human beings with human immune serum and hyperimmune serum from goats and monkeys.	Reports of icterus and serum reactions.
Smith et al. (1938)Smith HH, Penna HA, Paoliello A 1938. Yellow fever vaccination with cultured virus (17D) without immune serum. Am J Trop Med Hyg 18: 437-468.	Large scale vaccination with substrain 17D without animal serum.	Establishment of YF vaccine production at Oswaldo Cruz Institute.
Fox et al. (1942a)Fox JP, Lennette EH, Manso C, Aguiar JRS 1942a. Encephalitis in man following vaccination with 17D yellow fever virus. Am J Hyg 36: 117-142.	Investigate icterus outbreak after YF vaccination.	Recommendation for elimination of human serum from YF vaccine production and establishment of seed lot system.
Fox et al. (1942b)Fox JP, Manso C, Penna HA, Pará M 1942b. Observations on the occurrence of icterus in Brazil following vaccination against yellow fever. Am J Hyg 36: 68-116.	Investigate outbreak of encephalitis after vaccination with substrain 17D-NY 104.	Suspension of use of substrain 17D-NY 104.
Fox and Cabral (1943Fox JP, Cabral AS 1943. The duration of immunity following vaccination with the 17D strain of yellow fever virus. Am J Hyg 37: 93-120.)	Duration of immunity after YF vaccine, with several substrains and in several age groups.	Immunity persists after YF vaccine during at least four years in adults, lower immune responses in children less than 10 years of age.
Fox et al. (1943Fox JP, Kossobudzki SL, Cunha JF 1943. Field studies on the immune response to 17D yellow fever virus. Am J Hyg 38: 113-138.)	Choice of a new seed lot, dose-response, alternatives for vaccine administration (subcutaneous, intramuscular, intradermal).	This study was done before a previous study (Fox et al. 1942a), but published later. Human serum still used on the vaccine. A new seed lot was chosen, the substrain 17D-NY 104, that proved later to be neurotropic.
Fox et al. (1948)Fox JP, Kossobudzki SL, Cunha JF 1943. Field studies on the immune response to 17D yellow fever virus. Am J Hyg 38: 113-138.	Additional investigations on duration of immunity after YF vaccine.	Additional indications of lower seroprotection and duration of immunity in children.
Groot and Ribeiro (1962)Groot H, Ribeiro RB 1962. Neutralizing and haemagglutination-inhibiting antibodies to yellow fever 17 years after vaccination with 17D vaccine. Bull World Health Organ 27: 699-707.	Long term indications of seroprotection for 17 years.	This study was done in a region previously vaccinated with the 17D-NY 104 substrain.
Lopes et al. (1988)Lopes OS, Guimarães SSDA, Carvalho R 1988. Studies on yellow fever vaccine. III - Dose response in volunteers. J Biol Stand 16: 77-82.	Dose-response study.	A dose of 1000 plaque forming units (or its equivalent in LD₅₀) is more than enough for protection against YF.
Stefano et al. (1999Stefano I, Sato HK, Pannuti CS, Omoto TM, Mann G, Freire MS, Yamamura AMY, Vasconcelos PFC, Oselka GW, Weckx LW, Salgado MF, Noale LFO, Souza VAUF 1999. Recent immunization against measles does not interfere with the sero-response to yellow fever vaccine. Vaccine 17: 1042-1046.)	Investigate the interference between measles vaccine and YF vaccine.	There is no interference between measles vaccine and YF vaccine.
Freire et al. (2002Camacho LAB, Aguiar SG, Nascimento JP, Freire MS, Leal MLF, Iguchi T, Lozana JA, Farias RHG, Grupo Colaborativo para o Estudo das Vacinas de Febre Amarela 2005. Reactogenicity of yellow fever vaccines in a randomized, placebo-controlled trial. Rev Saude Publica 39: 413-420.)	Investigate immune response and duration of immunity after YF vaccine 17DD at egg-passage 43.	High levels of antibodies before YF vaccine inhibit the immune response. Persistence of immunity at 10 years after YF vaccination is questioned.
Camacho et al. (2004)Camacho LAB, Freire MS, Leal MLF, Aguiar SG, Nascimento JP, Iguchi T, Lozana JA, Farias RHG, Grupo Colaborativo para o Estudo das Vacinas de Febre Amarela 2004. Immunogenicity of WHO-17D and Brazilian 17DD yellow fever vaccines: a randomized trial. Rev Saude Publica 38: 671-678.	Immunogenicity of vaccine from new seed lot (17DD-013Z) compared to previous seed lot (17DD-102/84), World Health Organization (WHO) vaccine (17D-213/77) and placebo.	Advances on methodology and adherence to National Health Council norms. The new seed lot has adequate immunogenicity.
dos Santos et al. (2005)dos Santos AP, Bertho AL, Dias DC, Santos JR, Marcovistz R 2005. Lymphocyte subset analyses in healthy adults vaccinated with yellow fever 17DD virus. Mem Inst Oswaldo Cruz 100: 331-337.	Interspecific and specific immune response in vaccinated and revaccinated subjects.	YF vaccine induces immune response with activation and memory of humoral and cellular arms.
Camacho et al. (2005)Camacho LAB, Aguiar SG, Nascimento JP, Freire MS, Leal MLF, Iguchi T, Lozana JA, Farias RHG, Grupo Colaborativo para o Estudo das Vacinas de Febre Amarela 2005. Reactogenicity of yellow fever vaccines in a randomized, placebo-controlled trial. Rev Saude Publica 39: 413-420.	Reactogenicity of vaccine produced with new seed lot compared to previous seed lot (17DD-102/84), WHO vaccine (17D-213/77) and placebo.	The new seed lot is safe.
dos Santos et al. (2007)dos Santos AP, Bertho AL, Martins RM, Marcovistz R 2007. The sample processing time interval as an influential fator in flow cytometry analysis of lymphocyte subsets. Mem Inst Oswaldo Cruz 102: 117-120.	Study of lymphocyte subpopulations according to the time of processing of blood samples.	Flow cytometry by the lysis method may be done at times 0, 24 or 48 h after blood collection.
Martins et al. (2007)Martins MA, Silva ML, Marciano APV, Peruhype-Magalhães V, Eloi-Santos SM, Ribeiro JGL, Correa-Oliveira R, Homma A, Kroon EG, Teixeira-Carvalho A, Martins-Filho OA 2007. Activation/modulation of adaptive immunity emerges simultaneously after 17DD yellow fever first-time vaccination: is this the key to prevent severe adverse reactions following immunization? Clin Exp Immunol 148: 90-100.	Study of lymphocyte subpopulations in 10 healthy adults primovaccinated with 17DD vaccine.	The immune response is complex, activation and modulation seem to occur at the same time.
Santos et al. (2008)Santos AP, Matos DCS, Bertho AL, Mendonça SCF, Marcovistz R 2008. Detection of TH1/ TH2 cytokine signatures in yellow fever 17DD first-time vaccinees through ELISpot assay. Cytokine 42: 152-155.	T helper (TH)1/TH2 cells immune responses in 12 healthy adults vaccinated against YF.	After peripheral blood mononuclear cells ex vivo stimulation with 17DD vaccine, there is increase in interferon (IFN)-γ and interleukin-4, reaching maximum levels 15 days after vaccination.
Martins et al. (2008a)Martins MA, Silva ML, Elói-Santos SM, Ribeiro JGL, Peruhype-Magalhães V, Marciano APV, Homma A, Kroon EG, Teixeira-Carvalho A, Martins-Filho OA 2008a. Innate immunity phenotypic features point toward simultaneous raise of activation and modulation events following 17DD live attenuated yellow fever first-time vaccination. Vaccine 26: 1173-1184.	Phenotypical response of innate immunity in 10 adults after YF vaccine.	There is a balanced response of activation and modulation, studied in neutrophils, eosinophils, monocytes, natural killer (NK) and NKT cells.
Neves et al. (2009)Neves PCC, Matos DCS, Marcovistz R, Galler R 2009. TLR expression and NK activation after human yellow fever vaccination. Vaccine 27: 5543-5549.	Expression of toll-like receptor (TLR) and activation of NK cells in eight healthy adults vaccinated against YF.	NK cells are activated soon after vaccination against YF. IFN-γ is increased on day 15 after vaccination.
Melo et al. (2011)Melo AB, Silva MPC, Magalhães MCF, Gil LHV, Carvalho EMF, Braga-Neto UM, Bertani GR, Marques Jr ETA, Cordeiro MT 2011. Description of a prospective 17DD yellow fever vaccine cohort in Recife, Brazil. Am J Trop Med Hyg 85: 739-747.	Duration of immunity after YF vaccine.	17DD vaccine protects for at least 10 years, but with decreasing titres. Small sample.
Silva et al. (2011)Silva JRN, Camacho LAB, Siqueira MM, Freire M, Castro YP, Maia MLS, Yamamura AMY, Martins RM, Leal MLF, Grupo Colaborativo para o Estudo das Vacinas de Febre Amarela 2011. Mutual interference on the immune response to yellow fever vaccine and a combined vaccine against measles, mumps and rubella. Vaccine 29: 6327-6334.	Investigate the interference between YF vaccine and measles-mumps-rubella (MMR) vaccine when applied simultaneously.	Negative and reciprocal interference of YF, rubella and mumps antigens.
Luiza-Silva et al. (2011a)Luiza-Silva M, Campi-Azevedo AC, Batista MA, Martins MA, Avelar RS, Lemos DS, Camacho LAB, Martins RM, Maia MLS, Farias RHG, Freire MS, Galler R, Homma A, Ribeiro JGL, Lemos JAC, Martins MA, Eloi-Santos SM, Teixeira-Carvalho A, Martins-Filho OA 2011a. Cytokine signatures of innate and adaptive immunity in 17DD yellow fever vaccinated children and its association with the level of neutralizing antibody. J Infect Dis 204: 873-883.	Cytokines in children from nine-43 months of age vaccinated against YF.	Cytokine signatures show proinflammatory cytokines on subjects who sero-convert (SC) to YF vaccine and regulatory on non SCs. Revaccinated one year later, there was SC of previously non SCs with a proinflammatory pattern.
Luiza-Silva et al. (2011b)Luiza-Silva M, Martins MA, Espírito-Santo LR, Campi-Azevedo AC, Silveira-Lemos D, Ribeiro JGL, Homma A, Kroon EG, Teixeira-Carvalho A, Eloi-Santos SM, Martins-Filho OA 2011b. Characterization of main cytokine sources from the innate and adaptive imune responses following primary 17DD yellow fever vaccination in adults. Vaccine 29: 583-592.	Cellular sources of cytokines in 10 healthy adult vaccinated against YF.	Pattern of activation and modulation. Production of IFN-γ on day 7 by NK cells and on days 15 and 30 by T CD4+ (TH) cells.
Campi-Azevedo et al. (2012)Campi-Azevedo AC, Araujo-Porto LP, Luiza-Silva M, Batista MA, Martins MA, Sathler-AR, Silveira-Lemos D, Camacho LAB, Martins RM, Maia MLS, Farias RHG, Freire MS, Galler R, Homma A, Ribeiro JGL, Lemos JAC, Auxiliadora-Martins M, Caldas IR, Elói-Santos SM, Teixeira-Carvalho A, Martins-Filho O 2012. 17DD and 17D-213/77 yellow fever substrains trigger a balanced cytokine profile in primary vaccinated children. PLoS ONE 7: 1-11.	Cytokine profile in 80 children from nine-12 months of age, vaccinated with YF 17DD or 17D-213/77.	The YF reference vaccine from WHO has a immune response similar to the 17DD vaccine from Bio-Manguinhos/Oswaldo Cruz Foundation.
Martins et al. (2013b)Martins RM, Maia MLS, Farias RHG, Camacho LAB, Freire MS, Galler R, Yamamura AMY, Almeida LFC, Lima SMB, Nogueira RMR, Sá GRS, Hokama DA, Carvalho R, Freire RAV, Pereira Filho E, Leal MLF, Homma A 2013b. 17DD yellow fever vaccine. A Double blind, randomized clinical trial of immunogenicity and safety on a dose-response study. Hum Vaccin Immunother 9: 1-10.	Dose-response to YF vaccine in healthy young male adults.	YF vaccine from Bio-Manguinhos is so immunogenic in doses = 587 IU as in the usual dose of about 27,476 IU.
Melo et al.(2013)Martins RM, Homma A, Migowski E 2013a. Imunizações. In JR Coura, Dinâmica das doenças infecciosas e parasitárias, Guanabara Koogan, Rio de Janeiro, p. 431-443.	Memory after YF vaccine. Blood collected before vaccination two months and four years after vaccination.	YF promiscuous antigens may be better immunogens.

Vaccine	Reference	Rationale of the investigation	Comments
Measles	Schatzmayr et al. (1982)Schatzmayr HG, Nogueira RMR, Bermudez JAZ, Pinhão AT, Queiroz B, Venâncio LR, Assis CER, Shiraiwa T 1982. Serological response to measles vaccine (Schwarz strain) in a low-income population at Rio de Janeiro. Rev Microbiol 13: 242-249.	Seroconversion (SC) to measles vaccine by age in population of low social and economic status.	Supported the beginning of measles vaccination at nine months of age.
Measles	Oliva et al. (1986)Oliva OP, Chaves JRS, Loureiro MLP, Pereira LA, Homma A 1986. Vacina CAM-70 contra o sarampo produzida no Brasil. Avaliações de campo em crianças com 6-12 meses de idade. Boletim Epidemiológico 18: 121-126.	Immune response to measles CAM-70 vaccine in 341 children from six-12 months of age.	Measles CAM-70 vaccine seroconverted by neutralisation 100% of children = 9 months of age without maternal antibodies.
Measles	Camacho et al. (2000)Camacho LAB, Freire MS, Yamamura AMY, Leal ML, Mann G 2000. Estudo de soroconversão com formulações da vacina BIKEN CAM-70 contra sarampo. Rev Saude Publica 34: 358-366.	Dose-response to measles CAM-70 vaccine in children, three vaccine groups, with 5,000, 1,000 and 200 50% tissue culture infective dose (TCID₅₀).	The group of higher dose, 5,000 TCID₅₀ had better immunological response: 82% SC.
Measles	Lindgren-Alves et al. (2001)Lindgren-Alves CR, Freire LMS, Oliveira RC, Guerra HL, Da-Silva EE, Siqueira MM, Horta IM, Queiroz CC 2001. Pesquisa de anticorpos contra o sarampo em crianças infectadas pelo HIV após imunização básica. J Pediatr (Rio J) 77: 496-502.	Immune response to vaccine CAM-70 in 50 children, 21 perinatally infected with human immunodeficiency virus (HIV).	The immune response to measles vaccine is lower in HIV perinatally infected children, even after two doses.
Measles-mumps-rubella (MMR)	Boaventura et al. (2006)Boaventura AS, Stralioto SM, Siqueira MM, Ranieri TS, Bercini M, Schermann MT, Wagner MB, Silveira TR 2006. Prevalence of antibodies against measles, mumps and rubella before and after vaccination of school-age children with three different triple combined viral vaccines, Rio Grande do Sul, Brazil. Rev Panam Salud Publica 20: 299-306.	To compare the immune response to three different MMR vaccines in schoolchildren in the state of Rio Grande do Sul, Brazil.	Satisfactory immune response to the three vaccines, but the Leningrad-Zagreb mumps component seems to be a stronger immunogen.
Oral poliomyelitis (OPV)	Schatzmayr and Homma (1969Schatzmayr HG, Homma A 1969. Avaliação sorológica da vacina oral, tipo Sabin, contra a poliomielite, em região semi-rural. I. Formação de anticorpos em vacinados. Rev Soc Bras Med Trop 3: 317-322.)	Immune response to three doses of OPV in 114 children from three months-three years of age in a semi-rural area of the state of Rio de Janeiro, Brazil.	SC to OPV types 1 and 3 was not satisfactory; type 1 dose should be increased. Vaccine in study had 500,000 TCID₅₀(type 1), 200,000 (type 2) and 300,000 (type 3) per dose.
OPV	Schatzmayr et al. (1986)Schatzmayr HG, Maurice Y, Fujita M, Fillipis AMB 1986. Serological evaluation of poliomyelitis oral and inactivated vaccines in an urban low-income population at Rio de Janeiro, Brazil. Vaccine 4: 111-113.	To compare the immune response between OPV and inactivated poliomyelitis vaccine (IPV) in 155 children at two-six months of age.	IPV induces more serum antibodies, especially to type 3.
OPV	Patriarca et al. (1988)Patriarca PA, Palmeira G, Lima Filho J, Cordeiro MT, Laender F, Oliveira MJC, Dantes MCS, Risi Jr JB 1988. Randomised trial of alternative formulations of oral poliovaccine in Brazil. Lancet 27: 429-432.	Immune response to trivalent OPV (TVOP) with increased type 3 dose compared with previous formulation.	TVOP induces higher SC to type 3 with formulation containing double the dose of type 3 (600,000 viral particles).
Hepatitis B (HB)	Motta et al. (2002)Motta MSF, Mussi-Pinhata MM, Jorge SM, Yoshida CFT, Souza CBS 2002. Immunogenicity of hepatitis B vaccine in preterm and full term infants vaccinated within the first week of life. Vaccine 20: 1557-1562.	To compare the immunogenicity of HB vaccine between preterm and term newborns.	Preterm newborns need an additional dose of HB vaccine.
HB	Martins et al. (2004)Martins RM, Bensabath G, Arraes LC, Oliveira MLA, Miguel JC, Barbosa GG, Camacho LAB 2004. Multicenter study on the immunogenicity and safety of two recombinant vaccines against hepatitis B. Mem Inst Oswaldo Cruz 99: 865-871.	Safety and immune response to recombinant HB vaccine from Butantan Institute, state of São Paulo, Brazil.	The HB vaccine from Butantan Institute is equivalent to Engerix B from GlaxoSmithKline (GSK) in children and inferior, but acceptable for use in newborns, adolescents and young adults.
HB	Luna et al. (2009)Luna EJ, Moraes JC, Silveira L, Salina HSN 2009. Efficacy and safety of the Brazilian vaccine against hepatitis B in newborns. Rev Saude Publica 43: 1-6.	Safety and immune response of newborns to the HB vaccine from Butantan Institute.	The HB vaccine from Butantan Institute is equivalent to Engerix B from GSK in newborns.
HB	Moraes et al. (2010)Moraes JC, Luna EJA, Grimaldi RA 2010. Immunogenicity of the Brazilian hepatitis B vaccine in adults. Rev Saude Publica 44: 1-5.	Safety and immune response of adults to HB vaccine from Butantan Institute.	The HB vaccine from Butantan Institute is equivalent to Engerix B from GSK in adults from 31-40 years.
HB	Potsch et al. (2010)Potsch DV, Oliveira MLA, Ginuino C, Miguel JC, Oliveira SAN, Silva EF, Moreira RB, Cruz GVM, Oliveira ALVSM, Camacho LAB, Barroso PF 2010. High rates of serological response to a modified hepatitis B vaccination schedule in HIV-infected subjects. Vaccine 28: 1447-1450.	To investigate the immune response to HB vaccine in HIV-infected adults, with double the routine dose and in four doses.	The immune response to HB vaccine is satisfactory with the new schedule.
HB	Motta-Castro et al. (2009)Motta-Castro ARC, Gomes SA, Yoshida CFT, Miguel JC, Teles SA, Martins RMB 2009. Compliance with and response to hepatitis B vaccination in remaining quilombo communities in central Brazil. Cad Saude Publica 25: 738-742.	Adherence to vaccination and immune response to HB vaccine in quilombo communities in central Brazil.	Low adherence to vaccination schedule and lower immune response in males and people = 40 years of age.
HB	Potsch et al. (2012)Potsch DV, Camacho LAB, Tuboi S, Villar LM, Miguel JC, Ginuino C, Silva EF, Mendonça RMM, Moreira RB, Barroso PF 2012. Vaccination against hepatitis B with 4-double doses increases response rates and antibodies titers in HIV-infected adults. Vaccine 30: 5973-5977.	Immune response to HB vaccine in HIV-infected adults with double the routine dose and in four doses.	The immune response to HB vaccine is satisfactory with the new schedule.
Rotavirus	Mascarenhas et al. (2002a)Mascarenhas JDP, Leite JPG, Gabbay YB, Freitas RB, Oliveira CS, Monteiro TAF, Linhares AC 2002a. Rotavirus G serotypes and P[], G genotypes identified in cases of reinfection among children participating in a trial with rhesus-human reassortant tetravalent vaccine (RRV-TV) in Belém, Brazil. J Trop Pediatr 48: 93-97.	Reinfections by rotavirus in children vaccinated with rhesus-human vaccine.	Reinfections occur and may be severe.
Rotavirus	Mascarenhas et al. (2002b)Mascarenhas JDP, Linhares AC, Gabbay YB, Leite JPG 2002b. Detection and characterization of rotavirus G and P types from children participating in a rotavirus vaccine trial in Belém, Brazil. Mem Inst Oswaldo Cruz 97: 113-117.	Occurrence of rotavirus genotypes during clinical study with rhesus-human vaccine.	Many serotypes causing infections. P[8], G1, P[4] and G2 were found in 53% and 26.6% of infections.
Influenza	Santini-Oliveira et al. (2012)Santini-Oliveira M, Camacho LAB, Souza TML, Luz PM, Vasconcellos MTL, Giacoia-Gripp CBW, Morgado MG, Nunes EP, Lemos AS, Ferreira ACG, Moreira RI, Veloso VG, Siqueira MM, Grinsztejn B 2012. H1N1 pdm09 adjuvanted vaccination in HIV-infected adults: a randomized trial of two single versus two double doses. PLoS ONE 7: 1-11.	Immune response of HIV-infected adults to H1N1 pandemic influenza vaccine with adjuvant in two single or two double doses.	HIV-infected persons have a better immune response to H1N1 influenza pandemic adjuvanted vaccine after two doses and double the routine dose.
Quadrivalent papillomavirus (qHPV)	Giuliano et al. (2011)Giuliano AR, Palefsky JM, Goldstone S, Moreira Jr ED, Penny ME, Aranda C, Vardas E, Moi H, Jessen H, Hillman R, Chang Y, Ferris D, Rouleau D, Bryan J, Marshall JB, Vuocolo S, Barra E, Radley D, Haupt RM, Guris D 2011. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 354: 401-411.	Prevention of infection and lesions by vaccine types in heterosexual men and in men who have sex with men.	HPV is effective for the prevention of infections and lesions by papillomavirus in heterosexual men and in men who have sex with men.
qHPV	Moreira Jr et al. (2011)Moreira Jr ED, Palefsky JM, Giuliano AR, Goldstone S, Aranda C, Jessen H, Hillman RJ, Ferris D, Coutlee F, Vardas E, Marshall JB, Vuocolo S, Haupt RM, Guris D, Garner EIO 2011. Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescentes and young adults. Hum Vaccin 7: 768-775.	Safety and adverse events following qHPV vaccine.	qHPV vaccine has low reactogenicity and is safe.
qHPV	Palefsky et al. (2011)Palefsky JM, Giuliano AR, Goldstone S, Moreira Jr ED, Aranda C, Jessen H, Hillman R, Ferris D, Coutlee F, Stoler MH, Marshall JB, Radley D, Vuocolo S, Haupt RM, Guris D, Garner EIO 2011. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 365: 1576-1585.	Efficacy of qHPV vaccine against anal intraepithelial neoplasia in men who have sex with men.	qHPV vaccine reduces rates of anal intraepithelial neoplasia in men who have sex with men.
qHPV	Hillman et al. (2012)Hillman RJ, Giuliano AR, Palefsky JM, Goldstone S, Moreira Jr ED, Vardas E, Aranda C, Jessen H, Ferris DG, Coutlee F, Marshall JB, Vuocolo S, Haupt RM, Guris D, Garner EIO 2012. Immunogenicity of the quadrivalent human papillomavirus (type 6/11/16/18) vaccine in males 16 to 26 years old. Clin Vaccine Immunol 19: 261-267.	Immune response to qHPV vaccine.	qHPV vaccine induces immune responses in 97.4% of men; immune responses in heterosexual men are higher than in men who have sex with men.

Vaccine	Reference	Rationale of the investigation	Comments
Bacillus Calmette-Guérin (BCG)	Camacho and Klein (1990)Camacho LAB, Klein CH 1990. Risco de infecção tuberculosa entre escolares com alta cobertura pelo BCG. Bol Oficina Sanit Panam 108: 100-112.	To use BCG and purified protein derivative as a tool to evaluate prevalence of tuberculosis (TB) infections.	The prevalence of TB infections in areas of the state of Rio de Janeiro, Brazil, was 4.13%.
BCG	Barbosa et al. (2003)Barbosa T, Arruda S, Fernandes BD, Carvalho LP, Cardoso S, Cunha S, Barreto ML, Pereira SM, Rodrigues LC, Barral-Netto M 2003. BCG (Bacille of Calmette-Guérin) revaccination leads to improved in vitro IFN-γ response to mycobacterial antigen independent of tuberculin sensitization in Brazilian school-age children. Vaccine 21: 2152-2160.	Cytokines immune response to BCG revaccination in schoolchildren.	Production of interferon (IFN)-γ increases after BCG revaccination and may be a marker of protection against TB.
BCG	Oliveira et al. (2013Oliveira ES, Marinho JM, Barbosa T 2013. Interferon-gamma production by mononuclear cells in Bacille Calmette-Guérin-revaccinated healthy volunteers predicted long-term antimycobacterial responses in a randomized controlled trial. Vaccine 31: 3778-3782.)	Production of IFN-γ after BCG revaccination.	In the group with IFN-γ production increases of 3.3 or more after BCG revaccination the immune responses to mycobacterial antigens remained higher one year after vaccination than on the group with lower IFN-γ increases.
Diphtheria, tetanus and pertussis/Haemophilus influenzae Type b (DTP/Hib)	Clemens et al. (2003)Clemens SA, Azevedo T, Homma A 2003. Feasibility study of the immunogenicity and safety of a novel DTPw/Hib (PRP-T) Brazilian combination compared to a licensed vaccine in healthy children at 2, 4 and 6 months of age. Rev Soc Bras Med Trop 36: 321-330.	To investigate the possibility of mixing the conjugate, lyophilised, Hib vaccine from GlaxoSmithKline (GSK) with the DTP/whole cell pertussis (DTPw) vaccine from Butantan Institute, state of São Paulo, Brazil.	The Hib conjugate, lyophilised, vaccine from GSK, may be mixed with the DTPw vaccine from Butantan Institute.
DTP/Hib	Martins et al. (2008b)Martins RM, Camacho LAB, Marcovistz R, de Noronha TG, Maia MLS, dos Santos EM, Barbosa GG, da Silva AMV, de Souza PCNF, Lemos MCF, Homma A 2008b. Immunogenicity, reactogenicity and consistency of production of a Brazilian combined vaccine against diphtheria, tetanus, pertussis and Haemophilus influenzae Type b. Mem Inst Oswaldo Cruz 103: 711-718.	Consistency of production and non-inferiority of DTPw/Hib vaccine from Bio-Manguinhos/Oswaldo Cruz Foundation-Butantan Institute in comparison with DTPw/Hib vaccine with the DTP component from Butantan Institute and the Hib component from GSK.	Production of vaccine was consistent and the DTPw/Hib vaccine from Bio-Manguinhos/Butantan Institute is non-inferior to DTPw/Hib vaccine with the DTP component from Butantan Institute and the Hib component from GSK.
DTP/Hib	Matos et al. (2009)Matos DCS, Silva AMV, Neves PCC, Martins RM, Homma A, Marcovistz R 2009. Pattern of functional antibody activity against Haemophilus influenzae Type b (Hib) in infants immunized with diphtheria-tetanus-pertussis/Hib Brazilian combination vaccine. Braz J Med Biol Res 42: 1242-1247.	Functional evaluation of immune response to poli-ribosil-ribitol-phosphate (PRP) from DTPw/Hib vaccine locally produced.	The immune response is mainly IgG1 and PRP avidity increases during vaccination, reaching maximum levels after the third dose.

Vaccine	Reference	Rationale of the investigation	Comments
Malaria	Urdaneta et al. (1996)Urdaneta M, Prata A, Struchiner CJ, Tosta CE, Tauil P, Boulos M 1996. Safety evaluation of SPf66 malaria vaccine in Brazil. Rev Soc Bras Med Trop 29: 497-501.	Adverse events after SPf66 malaria vaccine in Brazil.	The malaria SPf66 vaccine is safe.
Malaria	Urdaneta et al. (1998)Urdaneta M, Prata A, Struchiner CJ, Tosta CE, Tauil P, Boulos M 1998. Evaluation of SPf66 malaria vaccine efficacy in Brazil. Am J Trop Med Hyg 58: 378-385.	Efficacy of malaria SPf66 vaccine in endemic area.	There was no evidence of significant protection after SPf66 malaria vaccine against Plasmodium falciparum and Plasmodium vivax.
Leishmania	Mendonça et al. (1995)Mendonça SCF, De Luca PM, Mayrink W, Restom TG, Conceiçao-Silva F, Da-Cruz AM, Bertho AL, Costa CA, Genaro O, Toledo VPCP, Coutinho SG 1995. Characterization of human T lymphocyte-mediated immune responses induced by a vaccine against American tegumentary leishmaniasis. Am J Trop Med Hyg 53: 195-201.	Immunogenicity of Leishmania pentavalent vaccine in two doses of 360 µg with seven days interval.	Seventy-four percent of volunteers became positive on Montenegro test after vaccination; cellular immunity developed only for the tegumentary disease, not for the visceral disease.
Leishmania	Marzochi et al. (1998)Marzochi KBF, Marzochi MCA, Silva AF, Grativol N, Duarte R, Confort EM, Modabber F 1998. Phase 1 study of an inactivated vaccine against American tegumentary leishmaniasis in normal volunteers in Brazil. Mem Inst Oswaldo Cruz 93: 205-212.	Immunogenicity and safety of Leishmania monovalent vaccine in one or two doses of 1.440 mg.	Induration area on Montenegro test was larger on the vaccinal groups than on placebo; vaccine is safe.
Leishmania	De Luca et al. (1999)De Luca PM, Mayrink W, Alves CR, Coutinho SG, Oliveira MP, Bertho AL, Toledo VP, Costa CA, Genaro O, Mendonça CF 1999. Evaluation of the stability and immunogenicity of autoclaved and nonautoclaved preparations of a vaccine against American tegumentary leishmaniasis. Vaccine 17: 1179-1185.	To compare immunogenicity of autoclaved and not autoclaved monovalent Leishmania vaccine.	Conversion, evaluated by the leishmanin skin-test (LST), was higher on the non autoclaved group than on the autoclaved group.
Leishmania	De Luca et al. (2001)De Luca PM, Mayrink W, Pinto JA, Coutinho SG, Santiago MA, Toledo VP, Costa CA, Genaro O, Reis AB, Mendonça SCF 2001. A randomized double-blind placebo-controlled trial to evaluate the immunogenicity of a candidate vaccine against American tegumentary leishmaniasis. Acta Trop 80: 251-260.	Immunogenicity of monovalent Leishmania vaccine in doses of 180, 360 and 540 µg, in two or three doses.	Conversion by LST test was 89.5% on the vaccine groups and 0% on the placebo group. Immunogenicity was higher on the group with 360 µg and two doses had immunogenicity similar to three doses.
Necator americanus (Na-ASP-2)	Diemert et al. (2012)Diemert DJ, Pinto AG, Freire J, Jariwala A, Santiago H, Hamilton RG, Periago MV, Loukas A, Tribolet L, Mulvenna J, Correa-Oliveira R, Hotez P, Bethony JM 2012. Generalized urticaria induced by the Na-ASP-2 hookworm vaccine: implications for the development of vaccines against helminths. J Allergy Clin Immunol 150: 169-176.	Safety and immune responses to Na-ASP-2 vaccine.	The Na-ASP-2 vaccine induced allergic reactions when given in an endemic area and study was interrupted.

Viral vaccines	Studies(n)	Licensed for use
Yellow fever	26	All
Hepatitis B	7
Quadrivalent papillomavirus	4
Oral poliomyelitis	3
Measles	4
Measles/mumps/rubella	1
Rotavirus	2
Influenza	1
Total	48
Bacterial vaccines
Bacillus Calmette-Guérin	3	All
Diphtheria, tetanus and pertussis/Haemophilus influenzae Type b (tetravalent)	3
Total	6
Parasitic vaccines
Leishmania	4	None
Malaria	2
Necator americanus	1
Total	7
All clinical studies	61	54/61 (88.5%)

[1] + Corresponding author: rmenezes@bio.fiocruz.br