Effectiveness of Vaccines
January 22, 2021Information
Marietta Vázquez, MD, professor of pediatrics (general pediatrics); vice-chair, diversity, equity, and inclusion, Department of Pediatrics; director, Yale Children's Hispanic Clinic (Y-CHiC), discussed the progression from efficacy in trials to effectiveness under “real-world conditions” for COVID-19 vaccines.
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- 00:00Thank you for for the for the invitation.
- 00:04I'll be. Brief,
- 00:07with the time that I have today,
- 00:10I'm going to be talking about effectiveness,
- 00:13so going from efficacy to effectiveness
- 00:15I I was a principle investigator in a
- 00:19randomized clinical trial for fieser
- 00:21an I've participated as a speaker in
- 00:24educational events for both Merck and Sanofi.
- 00:27So we're talking about going
- 00:29from efficacy to effectiveness.
- 00:32Strictly speaking,
- 00:32efficacy and effectiveness have
- 00:34very different meanings in the
- 00:37context of vaccine development.
- 00:39But there oftentimes they're
- 00:41used interchangeably, so,
- 00:42so in terms of similarities,
- 00:45they both present or represent the
- 00:49percentage reduction of disease amongst.
- 00:53People who are who are vaccinated but
- 00:55but there are obviously differences.
- 00:57Vaccine efficacy.
- 00:58As you've heard,
- 00:59the previous speakers refer to
- 01:01how well the vaccines perform
- 01:03under the most ideal conditions,
- 01:05and these are mostly randomized
- 01:07clinical trials.
- 01:07These are experimental studies
- 01:09that are considered the gold
- 01:10standard vaccine effectiveness,
- 01:12which I'll talk about in the few
- 01:14minutes that I have remaining refers
- 01:16to how well a vaccine performs under
- 01:19real world conditions under less than
- 01:22perfectly controlled circumstances.
- 01:23So what happens when a vaccine?
- 01:26Is given to individuals who have
- 01:28comorbidities, who are different ages.
- 01:30When the very strict criteria of
- 01:32all of us who've gotten are some of
- 01:35us have gotten our covid vaccine,
- 01:37I counting the interval.
- 01:39did I get this one? You know how many days?
- 01:42But as we know,
- 01:44in real in in real practice this
- 01:46is not often adhere to,
- 01:48so this slide shows you the.
- 01:51Scheme of randomized clinical trials.
- 01:53When you have a large group of
- 01:55susceptible individuals and those
- 01:57are randomized to receive or not
- 01:59receive the intervention in question.
- 02:00In this case it will be a vaccine and
- 02:03the direction of the study is looking
- 02:06forward in time to try to figure out.
- 02:09Which the proportion of.
- 02:11In each one of these groups of individuals
- 02:14who develop disease and is the vaccine works.
- 02:18Obviously, those who receive the vaccine
- 02:20are going to have lower rates of infection,
- 02:23but even though these studies
- 02:25are the gold standard,
- 02:26they have certain disadvantages.
- 02:28Their advantages, well, we've.
- 02:29I've mentioned before.
- 02:31They are the gold standard.
- 02:32Their experimental studies where the
- 02:34allocation or the intervention is
- 02:36given randomly, which minimizes bias,
- 02:38and for the most part,
- 02:40these studies are blinded, so it.
- 02:42Really ask helps you an unbiased
- 02:45ascertainment of the outcome,
- 02:47but they have disadvantages.
- 02:49They have poor statistical power for things,
- 02:52diseases that are buried rare.
- 02:54You need very large samples.
- 02:57They are very costly an oftentimes to
- 03:00selected population is studied again,
- 03:02sort of.
- 03:03Drawing parallels with Covid vaccine.
- 03:06Young individuals were not studied.
- 03:08Pregnant women were not studied.
- 03:11An individuals with significant
- 03:13comorbidities are oftentimes excluded.
- 03:14The follow-up is limited.
- 03:16Usually these are conducted for
- 03:18one of three years.
- 03:20Again, if you think of covid vaccine,
- 03:23everything was done much quicker,
- 03:25but for the most part there
- 03:27follow-up is limited,
- 03:28and this leads us to think
- 03:31about generalizability.
- 03:32How how did those results from the
- 03:35randomized clinical trial translate
- 03:37to the patient that we see and an?
- 03:40What is the the efficacy in in
- 03:43the general clinical setting?
- 03:45So, so the questions that remain
- 03:47on answers would be the efficacy.
- 03:49In actual practice, its efficacy,
- 03:51overtime, what happens five years later?
- 03:53What happens 10 years later and then when
- 03:56you start thinking of subgroup analysis,
- 03:58so populations if all of a sudden
- 04:01cardiac patients seemed to
- 04:03have a higher rates of disease,
- 04:05will it work as well in patients
- 04:07will have that type of comorbidity?
- 04:09As I mentioned,
- 04:11different age groups and ethnic groups
- 04:13which is very important especially now.
- 04:16In the face of COVID-19,
- 04:18where we see an infection that
- 04:21seems to to affect both in morbidity
- 04:24and mortality in in higher rates,
- 04:28certain a certain ethnic group.
- 04:31So effectiveness studies and now
- 04:32use the case control methodology,
- 04:34'cause that's the one that my
- 04:36collaborators and I have used for many,
- 04:38many years, is an observation.
- 04:40ULL study an in this case.
- 04:42This is the schematic of what
- 04:44case control study would be,
- 04:45and this is the study that we
- 04:47used to assess effectiveness.
- 04:49You select cases you select
- 04:50participants based on the outcomes.
- 04:52So the direction of the observation
- 04:54is completely the opposite.
- 04:55The cases are going to be the
- 04:57individuals who develop the
- 04:59disease in question controls other
- 05:00persons without the disease.
- 05:02And then you look backwards in time.
- 05:05To try to ascertain which proportion
- 05:07in each one of these groups developed,
- 05:10sorry were that were vaccinated,
- 05:12and if the vaccine is effective,
- 05:14then you would expect fewer of
- 05:16the cases to have been previously
- 05:18vaccinated as compared to the controls.
- 05:21And these studies have many advantages
- 05:23there statistically powerful
- 05:25with much smaller sample sizes,
- 05:27and I'll show you in some of the
- 05:30examples in the next few slides,
- 05:32you don't need longitudinal follow-up
- 05:34because there is no intervention.
- 05:36They are ethically acceptable
- 05:38because let's face it,
- 05:39after a vaccine is licensed
- 05:41and recommended for use,
- 05:43nobody is going to want to do a randomized
- 05:46trial where some people get something
- 05:48that is recommended and others are
- 05:51are going to are going to be withheld,
- 05:53something that that the
- 05:55scientific groups recommends,
- 05:56but they have disadvantages.
- 05:57They're not experimental,
- 05:58and there are susceptible to bias so.
- 06:02Is it really?
- 06:04When we now put this into into context
- 06:07with what's happening with Kovid vaccine,
- 06:09even though CDC and many others
- 06:11plan to track the effectiveness,
- 06:14we know that randomized clinical trials
- 06:16for covid vaccine have shown that this
- 06:20vaccine is highly highly effective.
- 06:22But it remains to be seen if indeed
- 06:25this efficacy of about 90% or higher
- 06:28in the ideal setting will will
- 06:31remained in everyday practice an we
- 06:33know that ongoing studies are needed
- 06:36to be able to address the questions
- 06:39that from the get go we have,
- 06:42but also unexpected relevant clinical
- 06:44clinical questions that that remain so.
- 06:46Our research team at Yale with
- 06:49collaborators over many years
- 06:51in other medical centers such as
- 06:53CDC and others have conducted
- 06:55studies of effectiveness of.
- 06:57Vaccines for multiple vaccines over the year,
- 07:00and I will share for this talk just
- 07:03one or two studies due to time,
- 07:06but show you how results of a study on
- 07:09this slide of effectiveness of varicella
- 07:12vaccine and as you can see here under 1000,
- 07:16subjects were included in the study,
- 07:18and even though the number of
- 07:20participants was small by enrolling cases,
- 07:23children with varicella and
- 07:25controls children without,
- 07:26we were able to assess the
- 07:28effectiveness of this vaccine.
- 07:30With great certainty the the method of
- 07:33measure that's used is the Max odds ratio,
- 07:36and that's what's used on
- 07:39case control studies,
- 07:40and we were able to assess the
- 07:44effectiveness of the vaccine.
- 07:46Furthermore,
- 07:46not only are we able to assess
- 07:49the overall effectiveness,
- 07:51but we are able to target
- 07:53important questions in subgroups,
- 07:55so again using the varicella
- 07:57vaccine as the example,
- 07:59we were able to evaluate the
- 08:01effectiveness by time elapsed from
- 08:03the time of vaccination in this study,
- 08:06led in part to changes in actual vaccine
- 08:10recommendation in the United States.
- 08:12Originally this vaccine was
- 08:14recommended just to receive one dose.
- 08:16And then with data from studies
- 08:19of effectiveness,
- 08:20the recommendation changed to include two
- 08:24doses routinely to Everett to everybody.
- 08:28Another one of the of the analysis
- 08:31that can be done an and we're done,
- 08:34is questions that arise that
- 08:36we didn't even think about.
- 08:38So in the varicella vaccine
- 08:40in after licensure,
- 08:41there were questions of whether what was
- 08:44the ideal age to give it to a child.
- 08:47Then again,
- 08:48at that point it would have been impossible
- 08:51to then go back to the randomized trial,
- 08:54but using the same methodology with
- 08:56data that were already accrued.
- 08:58Our team was able to answer this
- 09:01question an address whether the
- 09:04effectiveness in different groups
- 09:06by age were different,
- 09:08which ended up not not being different.
- 09:12Once a vaccine is licensed and
- 09:15recommended for the population in general,
- 09:17as I mentioned,
- 09:18it's unethical to conduct a
- 09:20randomized clinical trial,
- 09:21so figuring out whether using two
- 09:24doses was better than one would have
- 09:27been would have been impossible.
- 09:29But given the fact that when the
- 09:31recommendation for two doses came about,
- 09:34not everybody at once got to doses
- 09:36using the case control methodology,
- 09:39we were able to compare the effectiveness
- 09:42of individuals with Windows.
- 09:43Versus Versus 2 doses. So you know.
- 09:47Again,
- 09:47studies of Affectedness are very
- 09:50useful in being able to to acquire
- 09:53data like this one,
- 09:54and then another example from
- 09:57a different study. Is that?
- 10:00We can even conduct an be able to
- 10:02assess effectiveness for individuals who
- 10:05never received the vaccine themselves,
- 10:07and this study was done about
- 10:0910 years ago when the topic of
- 10:12vaccination during pregnancy was not
- 10:14well and graced by patients and not
- 10:17by the entire medical community,
- 10:19and the rates of influenza
- 10:21vaccination were low,
- 10:22and for this study we set
- 10:25out to evaluate whether
- 10:26one vaccine given to a pregnant
- 10:29mother would be able to protect both.
- 10:32The mother and the infant,
- 10:34which is not only very important
- 10:36in terms of protection,
- 10:37but also in terms of in
- 10:39terms of cost effectiveness,
- 10:41where you have one vaccine,
- 10:42being able to to protect two
- 10:44individuals for briefly for this study.
- 10:47We did very similar structure.
- 10:48A case control study where the
- 10:50cases were infants who were
- 10:52hospitalised due to influenza and
- 10:54controls were infants who were very
- 10:56similar who did not have influence.
- 10:58And again we look backwards in time.
- 11:01But rather than assessing.
- 11:03Influenza vaccine in the infants.
- 11:05It was different.
- 11:06We were assessing influenza vaccination in
- 11:09the in their mothers in the pregnant women,
- 11:12and again the data from this
- 11:15study greatly greatly.
- 11:16It showed that the vaccine given to
- 11:19a mother during pregnancy was highly
- 11:22effective in preventing her infant
- 11:24in the first six months of life from
- 11:28being admitted with lab documented influence,
- 11:30and an these data.
- 11:33Lead to increases in the rate of
- 11:37vaccination during pregnancy and
- 11:39I think have helped move forward
- 11:42the vaccination.
- 11:43Program so really just sum up.
- 11:48After randomized clinical trials are
- 11:50conducted in Vaccine Start license,
- 11:52an many other vaccines are going to
- 11:55continue to come through the market.
- 11:57There are questions and our
- 11:59certainties that we have.
- 12:01At this point.
- 12:02We can all have them in our heads whatever
- 12:05questions concerning Covid vaccine.
- 12:07There are certainly plenty of controversies,
- 12:10but we know that many other questions will
- 12:13come up questions that we didn't think about.
- 12:16An observation ull studies that
- 12:18assess effectiveness of the vaccines,
- 12:20such as case control studies,
- 12:22can be used successfully to address
- 12:25both immediate and long-term
- 12:26questions regarding these vaccines.
- 12:28Thank you very much.