Table of Contents

Volume 7, Issue 9

  September 2011

  Pages 891 - 991

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EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald W. Ellis and Eva M. Riedmann
Page 891
http://dx.doi.org/10.4161/hv.7.9.17964
PDF




NEWS, POLICY AND PROFILES

Open Access Article

News

Eva M. Riedmann
Pages 892 - 895
http://dx.doi.org/10.4161/hv.7.9.17965
Abstract | PDF

Successful chickenpox vaccination program: Near elimination of varicella deaths
FDA approves BOOSTRIX for adults over 65 years
Flu vaccine production expected to double by 2015
Positive Phase II results for Medicago’s pandemic flu vaccine
Mistrust against vaccines spreads to developing world
One step closer to universal Meningitis B vaccine
Innovative approach: Dynamic anti-heroin vaccine
Next-generation vaccine candidate on space voyage




PORTRAIT OF A LEADING VACCINOLOGIST

Open Access Article

From immunology to vaccinology: A journey of trial and error towards more rational design

Claire J. Boog
Pages 896 - 899
http://dx.doi.org/10.4161/hv.7.9.17966
Abstract | PDF

I was born in 1958 as the youngest of five in the south of the Netherlands. My father died a couple of months before my mother had to give birth to me so for her and the rest of my family it was a tough time. My mother was a very strong person with a positive attitude towards life. I inherited her ‘positive’ genes and she became a very important role model for me. I grew up wandering and playing around in nature. Guided by a high school teacher in Biology, I became fascinated by it at very young age. Instead of playing with dolls I used to study the behavior of animals in their natural environment (e.g. frogs, ants, other insects, mice etc). My family, especially my sisters, were not so amused by my hobbies since I used to take my entire collection of study objects home with me. I knew at a very young age that my fascination of all living creatures meant that I should become a biologist. I entered the public high school Koning Willem II in Tilburg.




REVIEWS

Open Access Article

Guidance for future HTA applications to vaccines: The HPV lesson

Giuseppe La Torre, Chiara de Waure, Giacomina Chiaradia, Alice Mannocci, Stefano Capri, Francesco Bamfi and Walter Ricciardi
Pages 900 - 904
http://dx.doi.org/10.4161/hv.7.9.16084
Abstract | PDF

The HTA is a multidisciplinary approach which is increasingly applied worldwide in order to support decision-makers in the introduction of health technologies. The application of HTA to vaccines is quite recent and linked to the increasing number of vaccines available or in development, especially to those intended to non pediatric immunization. In this article a description of the HTA approach used in the evaluation of the bivalent HPV vaccine in Italy is provided; moreover the reasons for keeping HTA process "alive" and identifying new or pending Public Health issues are discussed. In fact, the project raised questions and challenges about the standardization and sharing of HTA methods in Italy. Recently the need of updating the results is starting to be seen as urgent due to the evolution of scientific knowledge, the availability of the first results after technology introduction and the observed differences in vaccination strategies among Italian regions. Moreover in these last two years after the completion of the HTA project a number of new issues have risen in the Italian context as immunization rates, regional vaccination strategies, processes for vaccine selection and health economic issues.

Open Access Article

Universal protein vaccines against Neisseria meningitidis serogroup B, Streptococcus pneumoniae and influenza

Nicola Principi and Susanna Esposito
Pages 905 - 912
http://dx.doi.org/10.4161/hv.7.9.15986
Abstract | PDF

Traditional vaccines can only be really effective when the antigenic diversity or variability of the micro-organisms in the same bacterial species or viral family is no more than marginally different, and when protection is mainly dependent from antibody-mediated immunity. One solution is to identify the antigens common to all of the strains in a species or family that are significantly capable of eliciting inactivating antibodies. A number of attempts have recently been made to develop vaccines with conserved and highly immunogenic antigens made using various and sometimes highly innovative approaches. Although none of these vaccines has yet been licensed for human use, some have been widely studied in experimental animals and humans, and seem to increase the possibility of preventing previously uncovered or only partially covered infectious diseases. This review provides a detailed description of the most important new information concerning protein vaccines against influenza and meningococcal and pneumococcal diseases.




SHORT REPORT

Open Access Article

Anti-HBs antibody persistence following primary vaccination with an investigational AS02v-adjuvanted hepatitis B vaccine in patients with renal insufficiency

Murielle Surquin, Christian Tielemans, Joëlle Nortier, Michel Jadoul, Patrick Peeters, Miroslav Ryba, Ludek Roznovsky, József Domán, Xavier Barthelemy, Priya Diana Crasta, Marc Messier and Sophie Houard
Pages 913 - 918
http://dx.doi.org/10.4161/hv.7.9.16225
Abstract | PDF

Background: Three doses of the investigational AS02_v-adjuvanted hepatitis B virus (HBV) vaccine HB-AS02 have been shown to induce more rapid seroprotection and higher anti-HBs antibody concentrations in patients with renal insufficiency than four doses of FENDrix™ (HB-AS04), an adjuvanted HBV vaccine licensed in Europe for use in this population. This study evaluated persistence of immune response up to 36 months after primary vaccination.
Methods: In this open, international, Phase III follow-up study, 151 pre-dialysis, peritoneal dialysis and hemodialysis patients ³15 years of age received HB-AS02 at 0, 1, 6 months and 149 received HB-AS04 at 0, 1, 2, 6 months. Of these, 99 and 80 returned at Month 36, 76 and 62 of whom were eligible for inclusion in the Long-Term According-To-Protocol (LT-ATP) cohort for descriptive analysis of antibody persistence (mean age: 65.6 years). 
Results: At Month 36, 89.5% of subjects in the HB-AS02 group and 72.6% of those in the HB-AS04 group had anti-HBs antibody concentrations ³10 mIU/ml. Anti-HBs antibody concentrations were ³100 mIU/ml in 82.9% and 35.5% of subjects, respectively. Anti-HBs geometric mean antibody concentrations were higher in the HB-AS02 group over the 36 months of follow-up. An exploratory “time to boost” analysis confirmed that subjects who received HB-AS02 were 2.54 times more likely than those who received HB-AS04 to have anti-HBs antibody concentrations ³10 mIU/ml at Month 36 (p=0.013 [95% CI: 1.22, 5.31]).
Conclusion: HB-AS02 candidate vaccine induces high and persistent anti-HBs antibody levels in pre-dialysis, peritoneal dialysis and hemodialysis patients, potentially reducing the need for booster doses in this population.




RESEARCH PAPERS

Open Access Article

Antibody persistence ten years after first and second doses of 23-valent pneumococcal polysaccharide vaccine, and immunogenicity and safety of second and third doses in older adults

Daniel M. Musher, Susan B. Manoff, Richard D. McFetridge, Charles L. Liss, Rocio D. Marchese, Jennifer Raab, Adriana M. Rueda, Monica L. Walker and Patricia A. Hoover
Pages 919 - 928
http://dx.doi.org/10.4161/hv.7.9.15996
Abstract | PDF

In a study of older adults, first and second doses of 23-valent pneumococcal polysaccharide vaccine (PN23) induced IgG increases for all 8 vaccine serotypes tested. Participants (N=143, mean age 76 years) were re-enrolled to study antibody levels after ten years, and safety and immunogenicity of another PN23 dose. Ten years after first or second doses, mean IgG concentrations exceeded vaccine-naïve levels for 7 of 8 serotypes tested. Second and third doses administered at this time were generally well tolerated and were immunogenic, inducing similar postvaccination levels. Immunogenicity is preserved after multiple PN23 doses without evidence of a lower than expected immune response (i.e., without hyporesponsiveness).

Open Access Article

Co-circulation of G1, G2 and G9 rotaviruses in hospitalized patients in Bangladesh during 2006-2009

Mustafizur Rahman, A.S.M. Alamgir, Farjana Saiada, Zahid Hassan, Abu S.G. Faruque, Alejandro Cravioto, Tasnim Azim and Mahmudur Rahman
Pages 929 - 933
http://dx.doi.org/10.4161/hv.7.9.15988
Abstract | PDF

Rotavirus strain diversity in Bangladesh has been explored since 1985 and as seen in other parts of the world, rotaviruses have shown tremendous strain diversity overtime. Rotavirus antigen was detected in stool specimens using a solid-phase sandwich-type enzyme immunoassay. A multiplex reverse transcription polymerase chain reaction (RT-PCR) was performed for rotavirus G and P genotypes. This current study was carried out between 2006 and 2009 during which time 1,607 (23%) of 7,058 fecal specimens tested positive for group A rotaviruses with the highest incidence rate being observed in winter each year. Genotyping of rotaviruses showed a sharp decline in G2P[4] between 2008 and 2009 with a gradual increase in G1 and G9 strains. Since the Government of Bangladesh is planning to include rotavirus vaccine in the national immunization program, these data on rotavirus strain diversity should be taken into consideration for vaccine strain selection.

Open Access Article

The use of Streptomyces for immunization against mycobacterial infections

Nesty Olivares Arzuaga, Ailin Vila Granda, Juan Carlos Ramírez Gómez, María Elena Sarmiento García San Miguel, Juan Francisco Infante Bourzac, Yamilé López Hernández, Ana Lucrecia Elías López, Carlos Román Vallín Pólux, Leonora González Mesa, Rogelio Hernández-Pando and Armando Acosta Domínguez
Pages 934 - 940
http://dx.doi.org/10.4161/hv.7.9.16000
Abstract | PDF

Tuberculosis is one of the leading causes of mortality produced by an infectious agent. Different strategies including bioinformatics are currently being tested to identify and improve vaccines against tuberculosis. Comparative genome analysis between Streptomyces coelicolor and Mycobacterium tuberculosis suggest that both descend from a common Actinomycete ancestor. In this work, we suggest the use of Streptomyces as a live vector and explore the capacity of Streptomyces immunization to induce a protective response against mycobacterial infection. First, we compared the theoretical proteomes of S. coelicolor A3(2) with those of M. tuberculosis H37Rv and Mycobacterium bovis AF2122/97. This study showed a high similarity at the level of individual genes sequences with both bacteria sharing several membrane proteins. Then, we administered Streptomyces intraperitoneally to mice and determined its distribution by histopathology and culture; we did not find systemic dissemination. After administration of Streptomyces through different routes, we identified the most immunogenic, inducing strong humoral response, as denoted by the high serum antibody titers against this organism with cross reactivity to mycobacterial antigens. Finally, we evaluated the level of protection elicited by the inoculation of Streptomyces in Balb/c mice challenged with BCG. In these animals, lung bacillary loads were significantly lower than the control non-sensitized group.. These observations, along with Streptomyces’ potential for expressing foreign proteins, suggest that Streptomyces could be an advantageous vector in the design of new tuberculosis vaccines.

Open Access Article

Immunogenicity of two diphtheria-tetanus-whole cell pertussis-hepatitis B vaccines in infants: A comparative trial

Prasad S Kulkarni, Amita Sapru, Ashish Bavdekar, SS Naik, Moreshwar Patwardhan, Prajakt Barde and Anand N Pandit
Pages 941 - 944
http://dx.doi.org/10.4161/hv.7.9.15994
Abstract | PDF

Aim: Because of the high mother-to-infant transmissibility of hepatitis B (HB) infection, neonatal vaccination is necessary, but the further doses of HB vaccines can be combined with conventional diphtheria-tetanus-whole cell pertussis (DTPw) vaccines. We compared immunogenicity and reactogenicity of two tetravalent vaccines in Indian children, who after neonatal HB immunization, were vaccinated thrice with one of these vaccines.
Methods: In this open-label randomized study, 287 infants received a dose of an Indian- (Q-Vac^TM ) or European-made (Tritanrix-HB^TM ) tetravalent vaccine at age 6, 10, and 14 weeks. The ELISA antibodies were measured prior to the first and one month after the third dose. Immunogenicity was determined by measuring the seroprotection/seropositivity rates and geometric mean titres (GMT), whereas vaccine reactogenicity was elucidated with diary cards for 7 days following each dose. The potential unsolicited events were queried throughout the whole 3-month study period.
Results: Out of the 250 subjects who completed the study, 123 received the Indian and 127 the European vaccine. After 3 doses, the seroprotection/seropositivity rates were 99 % and 100% for diphtheria, 98% and 95% for tetanus, 89% and 94% for pertussis, and 100% and 100% for hepatitis B, respectively. GMT of tetanus antibodies was significantly higher with the Indian vaccine. Low-grade reactogenicity was rather similar in the two vaccine groups, the most common events being local pain, redness, swelling, fever, irritability, unusual crying, drowsiness, and non-specific gastrointestinal symptoms.
Conclusions: Since both immunogenicity and reactogenicity of the two vaccines were almost identical, the Indian vaccine poses a good alternative to the costlier competitor vaccines.

Open Access Article

The evaluation of the opinions and attitudes of healthcare personnel of the province Diyarbakir against influenza A (H1N1) and the vaccination

Funda Sevencan, Melikşah Ertem, Neval Özçullu, Vedat Dorman and Namık Kemal Kubat
Pages 945 - 951
http://dx.doi.org/10.4161/hv.7.9.16368
Abstract | PDF

In this study it was targeted aimed to evaluate the opinions and attitudes of healthcare personnel of the province Diyarbakir against Influenza A(H1N1) and the vaccination and to determine the undesired effects after the vaccination. In this descriptive study, 1691 healthcare personnel participated. The participants were asked about their opinions about being included in the risk group or not, status of advising and having Influenza A(H1N1) vaccination, reasons of having or not having the vaccination, their opinions and attitudes about the pandemic and influenza vaccine and the practices of the press and the Ministry of Health. Of participants, 49.6% stated that they advised pandemic influenza vaccination. Of the healthcare personnel, 35.3% stated that they had pandemic influenza vaccine. Age, sex, profession, having seasonal influenza vaccine , using Media and the Ministry of Health as a source of information were important factors for the status of advising and having Influenza A(H1N1)v vaccine. The healthcare personnel should be informed about the purpose and practices of protection programs. It might be suggested to use press, which is regarded as the most important communication media, in accordance with the conditions in order to achieve suitable risk communication with the society.

Open Access Article

Acceptability of school requirements for human papillomavirus vaccine

Jennifer S. Smith, Noel T. Brewer, Yuli Chang, Nicole Liddon, Sarah Guerry, Erica Pettigrew, Lauri E. Markowitz and Sami L. Gottlieb
Pages 952 - 957
http://dx.doi.org/10.4161/hv.7.9.15995
Abstract | PDF

We characterized parental attitudes regarding school HPV vaccination requirements for adolescent girls. Study participants were 889 parents of 10-18 year-old girls in areas of North Carolina with elevated cervical cancer incidence. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression. Approximately half (47%) of parents agreed that laws requiring HPV immunization for school attendance “are a good idea” when opt-out provisions were not mentioned. Far more agreed that “these laws are okay only if parents can opt out if they want to” (84%). Predictors of supporting requirements included believing HPV vaccine is highly effective against cervical cancer (OR=2.5, 95%CI:1.7-5.0) or is more beneficial if provided at an earlier age (OR=16.1, 95%CI:8.4-30.9). Parents were less likely to agree with vaccine requirements being a good idea if they expressed concerns related to HPV vaccine safety (OR=0.3, 95%CI:0.1-0.5), its recent introduction (OR=0.3,95%CI:0.2-0.6), or its potential to increase their daughters’ sexual activity (OR=0.4,95%CI:0.2-0.6). Parental acceptance of school requirements appears to depend on perceived HPV vaccine safety and efficacy, understanding of the optimal age for vaccine administration, and inclusion of opt-out provisions.

Open Access Article

Persistence of immune response to HPV-16/18 AS04-adjuvanted cervical cancer vaccine in women aged 15-55 years

Tino F. Schwarz, Marek Spaczynski, Achim Schneider, Jacek Wysocki, Andrzej Galaj, Karin Schulze, Sylviane M. Poncelet, Gregory Catteau, Florence Thomas and Dominique Descamps
Pages 958 - 965
http://dx.doi.org/10.4161/hv.7.9.15999
Abstract | PDF

The HPV-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) has been shown to induce a robust immune response in women aged 15-55 years (103514/NCT00196937). This follow-up study is the first report of persistence of immune response and safety profile through 48 months after vaccination in women aged 15-55 years. In this open-label, age-stratified Phase III study in Germany and Poland (105882/NCT00196937), healthy women aged 15-55 years received 3 doses of HPV-16/18 AS04-adjuvanted vaccine at 0, 1, and 6 months. Anti-HPV-16/18 seropositivity rates and geometric mean antibody titers (GMTs) were assessed by enzyme-linked immunosorbent assay (ELISA) in women aged 15-25 (n=168), 26-45 (n=186) and 46-55 years (n=177) from the time of first vaccination through 48 months. At Month 48, all subjects were seropositive for anti-HPV-16 antibodies and 99.4% were seropositive for anti-HPV-18. Antibody kinetics were as previously reported, with peak response at Month 7 followed by a gradual decline tending towards a plateau in all age groups. Anti-HPV-16/18 GMTs were sustained at Month 48 in all age groups, including women aged 46-55 years in whom GMTs were respectively 11-fold and 5-fold higher than natural infection levels. The vaccine exhibited a clinically acceptable safety profile in all age groups. In summary, the HPV-16/18 AS04-adjuvanted vaccine induces high and sustained immune responses in women aged 15-55 years, with antibody levels remaining several-fold higher than natural infection levels for at least 4 years after the first vaccine dose.

Open Access Article

Enterovirus infections in young infants: Are children still protected by maternal antibodies?

Liina Salur, Sami Oikarinen, Sisko Tauriainen, Maire Mandel, Heikki Hyöty and Raivo Uibo
Pages 966 - 971
http://dx.doi.org/10.4161/hv.7.9.16082
Abstract | PDF

Enterovirus infections are frequent in childhood and may be involved in development of several chronic diseases including type 1 diabetes. Maternal antibodies have a protective effect in young infants. It has been proposed that this protection is now vanishing due to decreasing circulation of enteroviruses in Western countries. We aimed to analyse the occurrence of enterovirus infections in 55 infants and to assess the protection provided by maternal antibodies to these children and the development of enterovirus antibodies in a prospective cohort study. In addition, the presence of enteroviruses was detected in faeces using RT-PCR and their serotype identified using VP1 region sequencing. Our results showed that before polio vaccination 12 of 194 faecal samples were positive for enterovirus RNA (coxsackieviruses A4, A5, A16 or echoviruses 13 and 16). After vaccination Sabin 1, 2 and 3 poliovirus strains predominated in stool samples. From birth to 6 months of age polio IgG and IgA increased in most of children whereas the levels of other enterovirus antibodies started to increase from 6 months to 24 months age. The frequency of maternal neutralizing antibodies was generally quite high but still 3 out of 8 infants had no maternal antibodies against the enterovirus serotype which they had in stool sample. This study shows that enterovirus infections are relatively frequent already before the age of 3 months. Considerable proportion of infants lack maternal antibodies against the virus causing their infection. The significance of this phenomenon needs to be evaluated in larger studies.

Open Access Article

Rubella seroprevalence among healthy individuals in Izmir, Turkey

Zafer Kurugöl, Levent Midyat, Ebru Türkoğlu and Tijen Ozacar
Pages 972 - 975
http://dx.doi.org/10.4161/hv.7.9.16370
Abstract | PDF

In order to assess immunity to rubella in Izmir, Turkey, a total of 600 persons of 1–70 years of age were selected with cluster sampling. Of the 597 subjects, 120(20.1%) was susceptible to the rubella according to their serum antibody levels. Of children 1 to 6 years of age, 50.9% was found to be serologically susceptible to rubella. Rubella protection rates showed a age-related increase, reaching maximum in the 15–19 age group, in which 98.1% of these subjects had antibody titre above the full protective level. Of the 126 females in the reproductive age group, only 4(3.1%) were found to be serologically susceptible to rubella. Logistic regression analysis showed that among the several independent variables, only age (p<0.001) was significantly associated with rubella protective antibody levels. Epidemiological studies should continue as the epidemiological characteristics of the disease may change depending on the uptake of MMR vaccination.




COMMENTARIES

Open Access Article

Anti-angiogenesis immunotherapy

Jonathan D. Schoenfeld and Glenn Dranoff
Pages 976 - 981
http://dx.doi.org/10.4161/hv.7.9.16407
Abstract | PDF

Tumors stimulate angiogenesis to meet increasing nutrient and oxygen demands. In addition to their role in vascular remodeling, pro-angiogenic cytokines and effector cells contribute to an immune-inhibitory environment associated with advanced malignancies. Despite the critical role of angiogenesis in tumor growth and dissemination, most anti-angiogenic cancer therapies have had only limited success selectively targeting one of the many factors implicated in this process. Similarly, the effectiveness of tumor immunotherapies has been limited by tumor-mediated escape mechanisms and immune suppression. By combining the two strategies, however, anti-angiogenic immunotherapy offers the possibility to more robustly inhibit tumor angiogenesis and simultaneously impact the immune-inhibitory effects of the pro-angiogenic tumor milieu. These potential synergies make the combination of immunotherapy and anti-angiogenic treatment a promising avenue for future research.

Open Access Article

Mucosally-targeted HIV-1 vaccines

Frank Wegmann
Pages 982 - 985
http://dx.doi.org/10.4161/hv.7.9.16505
Abstract | PDF

Thirty years into the HIV-1 epidemic, global efforts to make antiretroviral drugs broadly available and to foster behavioral changes by education show first signs of impact. Promising results are also seen in male circumcision studies, prompting several countries in sub-Saharan Africa to implement programs for the scale-up of medical male circumcision for HIV-1 prevention. Nevertheless a successful vaccine is required to significantly reduce the numbers of new infections per year, especially in countries in which other preventative strategies fail. Mucosally-targeted vaccines have received a lot of attention in the past decade because most major human pathogens are transmitted via a mucosal surface and recent data suggest that local pathogen-specific immunity might be required for protection against HIV-1 and other mucosally-transmitted infections. Despite this, there are only few market-approved mucosal vaccines available. One reason is that mucosal application of recombinant or purified antigen is inefficient at inducing systemic immune responses, which are often the central readout of preclinical vaccine trials. Therefore, focused research into novel mucosa-targeting adjuvants and antigen delivery systems along with exact delineation of correlates of mucosal immunity is of central importance for the development of successful vaccines against HIV-1 and other mucosally-transmitted infections.

Open Access Article

Improving the delivery of flu vaccine for the older people in times of economic recession: What social epidemiology tells us, and what else we need to know

Carlos Chiatti, Pamela Barbadoro, Giovanni Lamura, Francesco Di Stanislao and Emilia Prospero
Pages 986 - 988
http://dx.doi.org/10.4161/hv.7.9.16693
Abstract | PDF

Despite controversies, flu vaccine programs targeted to the older people are highly recommended and represent a common public health policy in industrialized Countries. Although demographic ageing will increase the share of population at higher risk of influenza, today economic recession is putting public budgets under pressure. Underfunding of prevention is becoming a larger problem, as prevention expenditure generally appears easier to cut compared to other front-line services like hospital bed-placement. In this commentary, after revising existing evidence and current economic scenario, we identify examples of promising topics for future research in the area of flu vaccination, with regard inter alia to: (1) the re-design of national vaccination programs (possible to be achieved also by using a comparative approach); (2) up to date economic evaluations of different national delivery systems; (3) the development of innovative interventions aimed at improving vaccine coverage and addressing also "hard-to-reach" segments of the older population.

Open Access Article

Adverse events following immunization: Easily preventable in developing countries

Ramesh Verma, Pardeep Khanna, Mohan Bairwa, Suraj Chawla, Shankar Prinja and Meena Rajput
Pages 989 - 991
http://dx.doi.org/10.4161/hv.7.9.16795
Abstract | PDF

The development of vaccines is one of the most important achievements in public health for reducing morbidity and mortality due to communicable diseases in children. As the incidence of vaccine-preventable diseases is reduced by vaccination, the general public becomes increasingly concerned about the safety associated with vaccines. BCG, DPT, Polio, Measles, Hepatitis B, Hib and their various combinations may cause transient minor adverse events including swelling, redness or soreness at the injection site, and low-grade fever, crying and irritability (in infants). The adverse events caused by an error/accident in vaccination programs as these relate to manufacturing, handling, cold chain maintenance, vaccination schedule or administration are program errors. They are generally preventable and detract from the overall benefit of the immunization program. AEFI (adverse event following immunization) surveillance allows the vaccination program to monitor the occurrence of adverse events and to differentiate the true from the false AEFI. The system will also ensures quality by monitoring program error, increasing public confidence, and helping to develop capacity to manage ‘crisis’ events within the vaccination program. These incidents, which result in needless deaths or life-threatening illness and damage to vaccination programs, should be generally preventable if proper reconstitution of vaccines and proper handling procedures are followed.