A randomized controlled trial comparing split and subunit influenza vaccines in adults in Colombia
Morales A.1, Arias Salazar J.2, Salazar Y.2, Garcia A.3, Arnoux S.3*, Arancibia A.3, Deroche C.3, Rey E.3
1 Centro
Médico Los Andes;
2 Siplas LTDA, Santa Fé de Bogota, Colombia;
3
Aventis Pasteur International, Lyon, France
Abstract
In a two-center, comparative trial, 344 adults were randomly assigned to
receive a single dose of inactivated split-virion (Imovax Gripeâ) or
sub-unit (Agrippal S1â) influenza vaccine (1999-2000 formulations).
For analysis, study groups were subdivided into adult (18-60 years old) and
elderly (over 60 years) subjects. Blood was drawn immediately before and one
month after vaccination, safety was evaluated using a blind-observer design
based on reporting of solicited and unsolicited adverse events. Both vaccines
were very well tolerated, had similar reactogenicity profiles, and elicited
fewer reports of reactions in elderly individuals. Post-vaccination Imovax
Gripeâ induced seroprotective antibody titers against the three
vaccine strains in 94-99% of adults and 88-97% of elderly subjects, compared
with 88-100% and 88-98%, respectively, of those given Agrippal S1â.
In conclusion, the split-virion and sub-unit influenza vaccines had similar
safety and reactogenicity profiles, and elicited satisfactory immunity in adult
and elderly subjects. However, higher post-vaccination geometric mean titer
(GMT) values in response to the B strain were seen with the split vaccine
Imovax Gripeâ, giving it a better overall immunogenicity.
Key words: Influenza vaccine; Split; Sub-unit; Adults.
Resumen
En un ensayo comparativo
realizado en dos centros, se asignaron de manera aleatoria 344 adultos para
recibir una dosis de vacuna contra la gripe de virus fraccionado inactivado
(Imovax Gripeâ) o de vacuna de subunidades (Agrippal S1â)
(formulaciones 1999-2000). Para el análisis, los grupos estudiados fueron
subdivididos en adultos (18-60 años) y ancianos (más de 60 años). La sangre fue
extraída justo antes y un mes después de la vacunación. La inocuidad fue evaluada utilizando un
informe sobre reacciones adversas, usando un diseño de observador a ciegas.
Ambas vacunas fueron muy bien toleradas, con perfiles de reactogenicidad
similares y desarrollaron escasas reacciones adversas en los individuos
ancianos. La vacunación con la Imovax Gripeâ indujo títulos de
anticuerpos protectores en suero contra las tres cepas de virus de la vacuna en
94-99% de los adultos y en 88-97% de los sujetos ancianos, comparado con
88-100% y 88-98%, respectivamente, con respecto a los que recibieron Agrippal
S1â. En conclusión: Las vacunas contra la gripe de tipo virus
fraccionado y sub-unidad presentan perfiles de inocuidad y reactogenicidad similares,
y desarrollan una inmunidad satisfactoria en sujetos adultos y en ancianos. Sin
embargo, luego de la vacunación, se observaron valores de medias geométricas de
los títulos ("GMT") contra la cepa B superiores con la vacuna de virus
fraccionado inactivado Imovax Gripeâ, dando una mejor
inmunogenicidad global.
Palabras clave: Vacuna. Gripe; Virus fraccionados; Subunidades; Adultos.
Influenza is an illness of viral origin characterized by a sudden onset of
an acute fever, myalgia, sore throat, cough and rhinitis, which spreads rapidly
throughout communities causing epidemics. Annual influenza attack rates average
10-20% of the worldwide population, but are higher in epidemic years1.
As well as the high social costs of influenza (absenteeism, family disruption,
care, etc.), in some cases influenza can lead to secondary bacterial pneumonia
or viral pneumonia and can exacerbate underlying medical conditions, ultimately
with fatal consequences. In the USA population as a whole, a total of 20 000-40.000 influenza-associated
deaths per year have been reported2. All age groups are
affected but the elderly are particularly at risk, most influenza-related
deaths and severe complications occurring in this age group3. In the
USA influenza-associated hospitalization rates are 40-60 per 100.000 in the 15-44
year age group, 20-40 among 45–64 year-olds increasing to 80-400 for those with
high-risk medical conditions in this age group, and 200- >1000 for those of
65 years or older4.
Up to now, most estimates of the excess morbidity and mortality
attributable to influenza have come from North America and Europe because of
the well-estab-lished surveillance programs in those countries. The importance
of influenza in countries with less temperate climates, such as Colombia has
only recently become appreciated5. Effective influenza vaccination
programs require extended surveillance, and at the present time there is a
growing network of National Influenza Centers operating in major cities of
South America6. In Colombia, after an influenza epidemic in 1996
that affected approximately 6 million people and caused at least 600 deaths, a
respiratory infection surveillance system was begun. Of the samples evaluated
between March 1997 and June 2000, Influenza A was characterized in 12% and
influenza B in 0.6%7.
Vaccination is the primary means of protection against illness caused by
influenza and is recommended for elderly persons, the immunocompromised and for
those who are especially exposed (large gatherings, public transport, etc.) or
liable to transmit influenza to an circle of high-risk acquaintances (in
residential care, healthcare workers, etc.)4, 8. Three types of
inactivated vaccines are used world-wide to protect against influenza:
whole-virion vaccines, split-virion vaccines containing the external and
internal components of the virus, and sub-unit vaccines composed of just the
external components of the virus (haemagglutinin and neuraminidase)9.
It has been proposed that the higher purity of sub-unit vaccines should make
them less reactogenic and better tolerated. Conversely, the whole-virion and
split-virion vaccines potentially contain more epitopes and so may be more
immunogenic. In Colombia two influenza vaccines with proven safety and
efficacy, a Triton X-100-split-virion vaccine, Imovax Gripeâ
(Aventis Pasteur, France)10, and a sub-unit vaccine, Agrippal S1â
(Biocine, Italy) are widely-used. As there is little comparative data available
to select between such vaccines in South America, especially in the elderly, we
performed a randomized study to compare the immunogenicity and clinical safety
of these two vaccines in two groups of Colombian subjects: adults, i.e. aged
from 18 to 60 years, and the elderly, i.e. aged over 60 years.
Methods
Study design
The study was conducted in two centers in Bogota, Colombia during November through December, 1999. The protocol was approved by the Ethics Committee of Bogota for center 1 (Centro Médico los Andes) and by the Asociación Colombiana de Infectología for center 2 (SIPLAS LTDA). The trial was conducted in accordance with the Declaration of Helsinki Good Clinical Practice, International Conference on Harmonization Guidelines11 and national and local requirements regarding ethical committee review and informed consent, applicable at the initiation of the study. All subjects gave written informed consent prior to study entry. A blind-observer design was used for collection of safety data, and serology assays were performed without knowledge of the vaccine received.
Subjects
Intended subjects were adults aged at least 18 years old, whose health
status was compatible with vaccination. Subjects were not enrolled if they met
any of the following exclusion criteria: allergy to one of the vaccine
components, acute febrile illness (oral temperature > 38°C) in the 72 hours
preceding inclusion, aggravation of existing, severe, chronic illness (heart
disease, respiratory disease, etc.), prior immunization with 1999-2000
influenza strains vaccine or any other vaccination during the 4 weeks preceding
inclusion or planned to be received between visit 1 and visit 2, auto-immune
disorders, immunocompromised, on immunosuppressive therapy, immunoglobulins in
the 3 months preceding inclusion, treatment with pituitary hormone extract,
women of childbearing age who were not under effective contraception or who
were at risk of becoming pregnant.
Subjects
were randomly assigned to receive a single dose of one of the two study
vaccines, the randomization being stratified according to the two defined age
groups (adult: 18 to 60 years, and elderly: over 60 years).
Vaccines
The influenza vaccines investigated in this study are both propagated in embryonated chicken eggs and inactivated with formaldehyde. The Triton-split influenza vaccine (Imovax Gripeâ, Aventis Pasteur, Lyon, France) and the subunit vaccine (Agrippal S1â, Biocine, Italy) contained in each 0.5 mL dose, 15 µg haemagglutinin from each of 3 strains recommended for the 1999/2000 formulations12: A/Sydney/5/97 (H3N2)-like strain (A/Sydney/5/97 – RESVIR 13 haemagglutinin), A/Beijing/262/95 (H1N1)-like strain (A/Beijing/262/95 – X127), and B/Beijing/184/93-like strain (B/Yamanashi/166/98). The vaccines also contained thiomersal (< 0.05 mg) and formaldehyde (< 30µg), and were presented in a buffered saline solution (up to 0.5 mL). Each subject received a single intramuscular injection of vaccine in the deltoid, administered by a study nurse to ensure that neither the subject nor the study investigators were aware of the nature of the vaccine administered (blind observer design).
Data collection
Immunogenicity
A minimum of 10 mL of blood was collected for immunogenicity analyses immediately prior to vaccination and 30 days (27 to 33 days permitted in protocol) after vaccination. Serum concentrations of anti-haemagglutinin (HA) antibodies were measured using the reference technique of haemagglutination inhibition13 at the WHO Reference Centre Laboratory, Claude Bernard University, Lyon, France. Titers were expressed as an inverse of dilution. The humoral response to the three vaccine viral strains was assessed for each of the two vaccines, based on geometric mean titer (GMT) of anti-HA antibodies (with 95% confidence intervals), geometric means of post/pre-vaccination antibody titer ratio (GMTR), seroprotection rate (percentage of subjects with a titer > 40 on day 30), seroconversion rate (percentage of subjects with a pre-vaccination titer < 10 and a titer > 40 on day 30), and significant increase (pre-vaccination titer > 10 and at least a four-fold rise on day 30).
Safety
Each subject was observed for 30 minutes for the appearance of any immediate reaction to vaccination. The subject was then provided with a diary card to record the date of onset, date of resolution and severity of any solicited (Table 4) or non-solicited local or systemic event occurring during the 30 day period between the vaccination and follow-up visits.
Statistical methods
The primary objective of the study was to compare the immunogenicity of
the two vaccines in terms of post-vaccination anti-HA GMT values 30 days after
vaccination. An analysis of variance (ANOVA) was conducted for each vaccine
viral strain. The log10 of the post-vaccination titers was the
dependent variable and the independent variables were vaccine group (2 classes:
Imovax Gripeâ and Agrippal S1â), age (2
classes: adults, i.e. aged between 18 and 60 years, and elderly, i.e. over 60
years old) and vaccine group by age interaction as independent factors. Based
on the estimation of the maximal standard deviation of the three vaccine viral
strains (0.80) and a clinically acceptable difference between GMT values (0.301
in log10), a minimal sample size of 153 subjects per group was
determined necessary in order to carry out 3 independent t-tests with an
individual a type-I error of 1.6% and a power of 80%. If one vaccine showed a
superior immunogenicity for at least one of the vaccine viral strains, it would
be considered globally superior to the comparator, unless both vaccines showed
superiority for a strain, thus allowing only a conclusion by strain.
Immunogenicity
analyses were performed in all subjects who complied with the protocol for the
duration of the study and had data for the two blood draws, but safety was
analyzed in a descriptive fashion in all subjects who received a vaccine dose.
Results
A total of 344 subjects were enrolled in the study. Imovax Gripeâ was administered to 172 subjects (83 adults and 89 elderly); 172 subjects received Agrippalâ (87 adults and 85 elderly) (Table 1). There were 43 subjects (19 vaccinated with Imovax Gripeâ and 24 vaccinated with Agrippal S1â) who were excluded from the per protocol analysis of immunogenicity for protocol violations, almost all due to missing blood samples or serology at one of the two visits. All subjects were included in the immediate safety analysis and safety data at the follow-up visit were available for 331 (166 in the Imovax Gripeâ group and 165 in the Agrippal S1â group). Demographic characteristics (male/female ratios of subjects and mean age) of the two groups were comparable (Table 1) for all analyses.
Immunogenicity
Analysis of the pre-vaccination blood samples revealed
that most subjects had elevated antibody titers for viral strain A/H3N2
(A/Sydney/5/97), 59.1% having seroprotective levels against this strain before
receiving vaccine (Figure 1). Anti-HA titers were lower for
the other two strains, 9.3% being seroprotected against A/H1N1
(A/Beijing/262/95) and 34.6% against B/Yamanashi/166/98. The distribution of
anti-HA antibody titers for all three strains was similar in the two vaccine groups
(Table 2).
One month after vaccination, substantial increases in serum anti-HA
levels were observed in all vaccine groups. Although there were no significant
differences between the two vaccines with regard to post-vaccination GMTs for
strains A/Sydney/5/97 and A/Beijing/262/95 (p = 0.271 and p = 0.716,
respectively), Imovax Gripeâ elicited signicaficantly higher
post-vaccination GMTs for strain B/Yamanashi/166/98 than Agrippal S1â in both the adult and elderly age groups (p < 0.0001) (Table
2). Therefore, according to the pre-established global statistical
hypothesis set up in this study, Imovax Gripeâ had the best overall
immunogenicity of the two vaccines.
Despite this difference, satisfactory immune responses
were obtained with both Imovax Gripeâ and Agrippal S1â.
One month after vaccination, at least 94-99% (range given for the three
strains) of the subjects in the 18-60 year age group who received Imovax Gripeâ
had seroprotective antibody titers compared with 88-100% in the Agrippal S1â
group. Although the proportional increases were not so great as in the younger
adults, as shown by the GMTR values in Table 3, the elderly
subjects had strong responses to vaccination, achieving seroprotective antibody
titers in 88-97% of the subjects aged over 60 years who received Imovax Gripeâ
and 88-98% in the Agrippal S1â group (Figure 1).
The percentages of initially seropositive subjects who achieved a significant
increase in anti-HA antibodies tended to be higher in subjects who received
Imovax Gripeâ for both age groups (Table 3).
Initially seronegative subjects also displayed good responses. In the 18-60
year age groups, seroconversion rates were 93% and 100% for H3N2, 92% and 88%
for H1N1, and 92% and 75% for B viral strains, with Imovax Gripâ and
Agrippal S1â, respectively. The rates in the elderly subjects were
essentially the same although there was a consistent trend for them to be
slightly lower; 86% and 88% for H3N2, 86% and 81% for H1N1, and 89% and 67% for
B, respectively.
Safety
The reactogenicity profiles for the two vaccines in the descriptive
analysis were sufficiently similar with regard to the frequency of solicited
events reported, that it would be unlikely that any significant differences
would have been found (Table 4). Reactions were mostly of
mild to moderate intensity, and the majority occurred and resolved within 5
days following vaccination. Only one immediate reaction was reported: one
subject vaccinated with Agrippal S1â experienced increased sweating
and hypotension within the 30 minutes of vaccination.
In the 1860 age group, 36.1% and 25.3% of the subjects who received
Imovax Gripeâ and Agrippal S1â, respectively, experienced
local reactions (Table 4). Local reactions were less
frequent in the older age group, with 7.2% and 11.5% of subjects who received
Imovax Gripeâ and Agrippal S1â experiencing at least one
local reaction in the 30 days after vaccination, respectively. Delayed systemic
reactions were reported by 33.7% and 35.6% of subjects in the 1860 age group
injected with Imovax Gripeâ and Agrippal S1â, respectively
(Table 4). Again the reaction rate was lower in the elderly
subjects, with 14.6% and 15.3% reporting a systemic reaction. Regardless of
vaccine group and the age category, the most frequently reported local reaction
was pain and the most frequently reported systemic reactions were headache,
asthenia and malaise.
One serious adverse
event was reported during this study. A diabetic female subject, 71 years of
age, was hospitalized for bronchospasm approximately one month after receiving
Agrippal S1â. The subject recovered with treatment and was
discharged. This event was judged as unrelated to vaccination by the
investigator.
Discussion
On a global perspective, influenza vaccination is re-commended in many countries
worldwide including Western Europe, the United States, Canada, Australia, New
Zealand, Korea, Japan, Singapore, Central Europe and Latin American countries.
Most of these countries recommend vaccination to anyone six months of age or
older who is at increased risk for complications of influenza and those who are
in close contact with the at-risk population4, 5. In the United
States, the Advisory Committee on Immunization Practices (ACIP) issued the
recommendation in 2000 to include vaccination of all persons aged 50 and over4.
This represents a lowering of the initial recommended target group age of 65
years or older since it had been noted that a substantial proportion (24-32%)
of people between 50 and 64 years of age have one or more chronic medical
conditions that place them at high risk for influenza-related hospitalization
and death.
Both vaccines investigated in this study have been available for over a
decade, the split virus Imovax Gripeâ since 1968, and subunit
Agrippal S1â since 1987, and both have proved to be efficacious in
preventing influenza or in lessening the severity of the illness. The relative
merits of each type of vaccine are the subject of much debate. Essentially, the
subunit vaccines are promoted on the basis of a more "purified" product being
less reactogenic, while supporters of inactivated split vaccines suggest that
the wider range of epitopes available make such vaccines more immunogenic.
However, there is little published information on the immunogenicity of these
vaccines assessed in direct comparative studies in a given flu season,
particularly in the important target population of elderly adults. Furthermore,
prior to 1995 Imovax Gripe was prepared using a "Tween-ether" disruptive agent
for the splitting, before this agent was replaced with Triton X-100 in order to
improve industrial safety10. Thus data from studies published up to
1995 represents the vaccine prepared using the "old" process.
Since it is widely believed that the elderly have a diminished ability
to produce antibodies in sufficient quantity after vaccination14, we
investigated the safety and immunogenicity of the vaccines in two age groups:
adults from 18 to 60 years of age, and those aged over 60 years. In our study,
we found high pre-vaccination antibody titers for the A/H3N2 and the
B/Yamanashi/166/98 strains in both vaccine groups, giving seroprotection rates
of 52%-62% and 29%-47%, respectively, compared to a rate of 8-11% against the
A/H1N1 strain. This is indicative of previous vaccination or previous
infection, either of which were possible since these same strains were present
in the recommended formulation for the 1998-1999 flu season the previous year.
Nevertheless, substantial increases in GMTs from pre- to post-vaccination were
observed for all strains in both groups (ranging from 4-fold to 35-fold for a
given strain and vaccine), signifying that even in the presence of protective
antibody titers, the vaccines elicited a strong booster-effect.
Over 92% of the initially seronegative subjects in the 18-60 age group
achieved seroprotective titers after vaccination. Excellent responses were also
observed in the elderly-over 85% seroconverting and 55-75% displaying a
significant increase in antibody titers. These immunogenicity data correlate
with the clinical results obtained with influenza vaccination in the elderly14-16.
Conflicting results have been reported regarding the association of
increased age and influenza vaccine response; however an in-depth review of
relatively old literature (1968-1988) revealed that such an association has yet
to be established17, and more recent studies have not found any
statistical difference between age groups with regard to vaccine response18,
19. The vaccine has been shown to be effective in preventing secondary
complications and reducing the risk for influenza-related hospitalization and
death in elderly populations if the vaccine strain is similar to the epidemic
strain19, 20. A meta-analysis and review of the literature (up to
1995) concluded that influenza immunization is an indispensable aspect of the
care of the elderly21. Another meta-analysis based on the literature
from 1975 to 1995 (and hence excluding the "new" Imovax Gripe) concluded that
there was no effective difference in seroresponse to sub-unit or split vaccines
in adults or the elderly22.
Overall, because of the higher response against the B strain, the best
immunogenicity in terms of post-vaccination GMT values was seen in response to
the split vaccine Imovax Gripeâ, but both vaccines fulfilled the
European requirements for influenza vaccines in the elderly13. These
results are consistent with other studies that have reported an overall
superior immunogenicity of split viral vaccines compared with subunit vaccines
for at least one vaccine strain, although the differences were not always
statistically significant22, 23.
Despite claims that, in general, the safety profile of a subunit vaccine
is superior to that of a split vaccine, the present study confirmed the safety
and good tolerability of both types of influenza vaccine, which exhibited
similar reactogenicity profiles. This result is similar to that observed in a
recent evaluation of the safety of nine influenza vaccines in over 16 000
volunteers of 65 years of age or older in Italy, in which the reactogenicity of
Vaxigripâ (equivalent to Imovax Gripeâ) was at least as
good as the best subunit vaccine studied24.
Injection site soreness was the most frequently reported adverse event
following vaccination, as has been reported in other trials25-27. In
our study local reactions were reported less frequently in the older age group
for both vaccines. Similarly, systemic events were also reported twice as
frequently in the younger age group. This same trend was confirmed in a similar
clinical trial evaluating the 1999-2000 flu vaccine in which 34% of the
subjects in the 18-60 years age group experienced local reactions and 23%
experienced systemic reactions (Aventis Pasteur unpublished data). In the over
60 years age group, 21% experienced local and 3% experienced systemic
reactions. A similar reactogenicity profile was observed with Vaxigripâ
in French subjects from 8 to 85 years of age10.
In a large-scale study of over 9 000 volunteers aged 65 and older
influenza vaccination appeared very safe and well tolerated16. No
serious adverse events were reported by any volunteer. Most reported adverse
events were local injection site reactions that occurred in the first 2 days
after vaccination; 81% of the reactions subsided within 3 days. Only 1.8% of
the vaccinees reported fever. Local reactions considered disabling were rare
(4%) and most subsided within 3 days. In terms of a risk-benefit analysis, the
advantages of immunization against influenza more than compensates for the
minor discomfort associated with vaccination.
Influenza vaccination is
associated with substantial clinical and economic benefits in adults of all
ages including lower rates of hospitalization and reduced risk of death as well
as cost savings28, 29. Moreover, vaccination is effective in
preventing illness in all age groups3. Nevertheless, influenza
vaccines are still underused in almost all countries. It is important that
health care providers communicate the proven efficacy and low reactogenicity
profile of these vaccines in order to increase public confidence and hopefully
increase vaccination rates.
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Recibido:
20de noviembre de 2002
Aceptado:
29 de setiembre de 2003