Comparative case study of poor and good public health practice: Vaccine trials

Introduction:

Vaccines prevents diseases, disability and mortality from diseases like diphtheria, cervical cancer, pneumonia,
rotavirus diarrhea and eradicated smallpox. It is considered the world’s most successful and cost effective health
intervention (WHO,2018). Vaccines has major public health benefits as it participates in reducing inequity and poverty
( Andre et al, 2008).

Clinical researches are crucial to improve the existing vaccines and develop new ones to keep responding to the
diseases including emerging and reemerging diseases such as Ebola virus. This is globally sponsored by the Global
Vaccine Action Plan (GVAP) goals: new and improved vaccines are to be launched, and to develop vaccines and
technologies for the future generations via researches (WHO, N.D). Clinical researches on human subjects are very
sensitive and needed to be binding with the ethical guiding documents and principles to preserve human rights and
facilitate the pursuit of common good, equity and global health (Skolnik, 2015).

Summary of 2 vaccine trials:

A randomized double blind placebo controlled trial to test the efficacy of a monovalent human bovine (116E) Rotavirus
vaccine (ROTAVAC) against Rotavirus gastroenteritis-RVGE- and its tolerability in Indian infants. It is a multicenter
phase III trial conducted in 3 sites between urban (Delhi) and rural (Pune and Vellore). The subjects were 6799 infants
of 6 to 7 weeks of age distributed as 60% from urban and 40% from rural areas. 4532 and 2267 subjects were
randomly assigned to receive the vaccine and salt water injections as a placebo, respectively. 3 doses of the vaccine/
Placebo were given to the assigned groups at age of 6, 10 and 14 weeks. This study took place during the period of
2011 till 2013 ( Bhandari et al, 2014).

Costa Rica vaccine trial (CVT) was conducted to evaluate the efficacy of the licensed HPV-16/18 AS04-adjuvanted
vaccine against HPV16/18 in prevention of cervical cancer precursor when given in less than 3 doses. This was aiming
to overcome the cost barrier of implementing the 3 dose schedule in some countries ( Kreimer, 2015). It was a
community based double-blinded randomized controlled phase III trial on 7466 consenting women aged 18-25 years
old meeting the eligibility criteria. 80% received 3 doses, 12.4% received 2 doses and 7.4% received one dose. The
vaccine was given at the time of enrollment, 1 month later and 6 months after enrollment. Hepatitis A vaccine was
used as a placebo in this study. The participants’ recruitment was complete in Dec 2005 and the study took place in
Guanacaste, Costa Rica which is known historically for the high prevalence of cervical cancer ( Herrero et al, 2008).

Ethical issues within and its management:

ROTAVAC trial has targeted infants who are considered as a vulnerable group due to their age and immunity criteria. In
addition, being an infant in a country where the incidence of diarrhea and specifically rotavirus gastroenteritis is high,
mounting the mortality to 22% of all diarrhea related deaths in less than 5 years old children, contributes to the
vulnerability status for this age group (Bhaumik, 2013). However, Hence the vaccine is ought to benefit this age group,
it could not be tested on older age group as per the concept of the age de-escalation for this phase of vaccine trial
( Kulkarni, 2013). And it is fair as per the fairness principle of the declaration of Helsinki ( World Medical Association,
2018).

The selection of the control and the type of placebo is a common ethical principal between the two mentioned trials.
However, its managed differently. ROTAVAC trial used salt water as a placebo to gauge the efficacy and safety of the
vaccine, though there were 2 licensed rotavirus vaccines (RotaTeq from Merck and Rotarix from GlaxoSmithKline)
available by then and used in many countries as part of the immunization program per WHO advice (Bhaumik, 2013).
The trial put the infants in an unnecessary risk by using an inappropriate placebo instead of using one of the licensed
vaccines as a control. This presents a serious breach of one of the international ethical principles as per the declaration
of Helsinki. Moreover, it is breaching the beneficence and non-maleficence principles of the biomedical ethics as per
the Belmont report: Beneficence for the participants is not preserved whereas the harm is not minimized for those
infants though of the possibility to do so.( U.S. National institute of Health, N.D).

For these reasons, ROTAVAC trial is found to be poor ethical public health practice, though there are other ethical
principles that were respected. The trial is ought to contribute greatly to the community and health system once the
vaccine is licensed, as it brings in economic relief and so, a valid social benefit. If licensed, it will dramatically drop the
cost of the population vaccination against rotavirus and the vaccine would become affordable for many low- middle
income countries. Rotavirus vaccines produced by GlaxoSmithKline and Merck are 2398 Rs and 2700 Rs per course
respectively. Meanwhile ROTAVAC from the Indian company of Bharat Biotech would be of about 189 Rs per course
(Johari, 2017).

Furthermore, the trial observed the beneficence principle by maximizing the benefit for the participants as other
childhood vaccines (DPT, Hib, Hep B, OPV) were given concomitantly. ROTAVAC is of beneficence though of its modest
efficacy of 50-60% which is found to be in line with the efficacy of the other two licensed rotavirus vaccines from GSK
and Merck. Also, considering the fact that the tested ROTAVAC vaccine is to be applied in countries with high
incidence of rotavirus diarrheas and related mortality like India, then 50-60% of efficacy would be of a great benefit in
reducing the disease morbidity and mortality and so improve the DALYs (Madhi & Parashar, 2014).

For the HPV16/18 vaccine trial, no participants vulnerability is detected. The group is to benefit from the trial and so is
the community/country where it is conducted. Regarding the selection of the control with placebo use: HPV16/18
vaccine trial did not breach the declaration of Helsinki , though it used Hepatitis A vaccine as a placebo. This is
because it was one of the first vaccines to be developed for HPV and its efficacy was being tested. The first HPV
vaccine ever licensed was in 2006, i.e. after this vaccine trial was conducted (World Health Organization, 2017). Non-
existence of alternative licensed vaccine justified the use of the placebo.

The HPV16/18 vaccine trial observed the non-maleficence principle by following the selection and exclusion criteria
which are ought towards avoidance of harming participants. For example, pregnant women were excluded from the
trial to avoid harm to the participant and the fetus. Ancillary health care and rigorous follow up was provide for the
participants throughout the study and the 4 years follow up period. Excluded women from the trial due to cytological
cervical change or cancer in the cervix were provided medical care accordingly, contributing into the distributive
justice to all of the screened participants. Justice and respect of autonomy were observed via the fair selection of the
participants which was done by home visits to all of the houses in the study area and eligible women were invited to
participate. Participants autonomy was further respected when the informed consent was distributed in written to the
participants and given the chance to read it and discuss at home with their families if they wish before discussing it
with the research interviewers and accepting it. Costa Rica vaccine trial of HPV16/18 vaccine is found to be a good
ethical public health practice due to the respect of the above mentioned principles and no apparent breach is
observed ( Herrero et al, 2008).

Recommendations:

The ethical guidelines provide direction and not meant to prevent flexibility and innovation in researches (Slack, 2015).
It is recommended to follow them and observe the following:

 Before conducting the trial: carry a proper study and analysis of pre-existing data and vaccines related to the
intended research ( Lurie and wolfe, 1997).
  Community engagement, including the local health system staff, before and throughout will enrich the study
and prevent possible community barriers and misunderstanding that can affect the research.( Kulkarni, 2013;
Molyneux, 2017).
 Fair selection of the participants. Participants recruitment should be balanced in terms of vulnerable group
participation as they will have to be protected from coerced participation but also given the chance to benefit
from the research and its result, which can be specific to the beneficence of this vulnerable group (Fouka and
Mantzorou, 2011)
 Research design: the research has to be needed and justified for the scientific and societal benefit. Selection of
the control and placebo is to be carefully studied. Age de –escalation concept in vaccine trial is to be well
observed. (Kulkarni, 2013).
 Informed consent: has to be informed and non-coerced. It feeds into the respect of autonomy. The
information provided are to be understandable to the participants, i.e. to be in their native language, using
pictures, diagrams, discussions or other facilitating method (Kulkarni, 2013; Molyneux, 2017). It is of moral and
legal value and can be obtained written or even audio-visualized as long it preserves the participants right and
wellbeing ( Gupta et al, 2018). It might be needed to obtain the informed consent during each step of the
research as well to ensure the moral fulfillment of the consent and give the participants the space to withdraw
if they decided to ( Linedegger and Richter, 2000).
 The study design is to be thoroughly tested against the main 4 ethical principles of research. The above
mentioned recommendations usually feed into these principles.

Conclusion:

Clinical researches on human subjects are ethically challenging. Vaccine trials peculiarly difficult with ethical issues due
to their inherent nature. However, the will to strive towards fulfilling the ethical principles in implementing the
researches is crucial. Lessons learnt from previous researches and continuous work on the ethical consideration paves
the way forward.