Vaccines in Older Adults

January 22, 2021

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Albert C. Shaw, MD, PhD, professor of medicine (infectious diseases) discussed issues related to the use of vaccines in older adults, including how age affects the immune response.

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00:00I like to do is first thank
00:03Dean Browning organizers for
00:04inviting me to participate.
00:05I'm going to do a quick
00:08overview of this area.
00:09Some of the work that we've
00:11been doing here at Yale and
00:13also give an overview at the
00:15end of current approaches to
00:17enhancing the vaccine responses in
00:19older individuals. OK, so this
00:21is kind of our demographic
00:23imperative. The aging of the Post War Two
00:26baby boom generation in which the
00:28first members of this generation
00:30began turning 65 about 10 years ago.
00:33There showing the red in this US Census
00:36data plot with increasing age and the
00:38Y axis and you see how the shape of
00:41this population distribution changes
00:43substantially from 1980 to 2040,
00:45and it's estimated that everyday
00:4710,000 more members of the baby
00:49boom generation are turning.
00:5165 is going to continue until around 2013.
00:54By 2035, it's estimated that the
00:56number of adults over age 65 will
00:59exceed that of children for the
01:01first time in US history. Is
01:04obviously has a lot of implications for
01:07healthcare. Older adults are at
01:09increased risk for morbidity and
01:11mortality from infectious diseases
01:13and have decreased responses to vaccination
01:16in a typical influenza vaccine season,
01:18about 90% of the mortality occurs
01:21in older adults over age 65.
01:23The effectiveness of the seasonal vaccine.
01:26This is CDC data extending back about
01:2915 years and showing all comers can be
01:33substantially reduced in older adults,
01:36sometimes with vaccine efficacies
01:38with a lot of variability,
01:40but sometimes extending into the teens,
01:43or even worse in older individuals.
01:46And we've also seen a similar effect in
01:49terms of mortality during the SARS Co V2.
01:53COVID-19 pandemic with about 80%
01:55mortality occurring in older adults and
01:58it's encouraging as on Yemen mentioned
02:01that the initial news seems to be good
02:04from some of the vaccine platforms.
02:06So how does age affect the immune response?
02:09This seems to affect all phases of
02:12the immune response and the adaptive
02:15immune system is on the Emma alluded to,
02:18there is decreased antibody titers
02:20following vaccination,
02:21correlating with decreased levels
02:23of antibody secreting cells.
02:24Post vaccine work from defining Bloomberg
02:27and Daniel Frasca is also shown.
02:29Decreased expression of activation
02:31to citing deaminase,
02:32an essential protein for heavy
02:34chain class switching and somatic
02:36hypermutation affecting the quality
02:38of the antibody response.
02:40The T cell compartment is dominated
02:42by the effects of thymic involution,
02:44which starts to occur in young adulthood,
02:47resulting in markedly decreased
02:49cellularity in the thymus compared
02:51to a thymus from a child.
02:53And really,
02:54in humans there's very little thymic
02:56activity to speak of in older adults,
02:59and the vast majority of the T slim
03:02partners maintain exclusively by
03:04homeostatic perforation in the periphery.
03:06This is obvious effects on the diversity
03:09of the potential diversity of the
03:11vaccine response or response to infections.
03:14In addition,
03:15there have been multiple signal
03:17transduction defects identified in
03:19the T cell lineages affecting the
03:21quality of T cell receptor signaling.
03:24In addition,
03:25alterations in other pathways
03:26such as adenosine sibling,
03:28that influence survival of memory,
03:30T cell populations and also the function
03:33of follicular helper T cells which are
03:36implicated in the antibody response.
03:38In the innate immune system there's a similar
03:41paradoxical chronic inflammatory state,
03:43termed inflammation by Claudio Franceschi.
03:45You'll see that in the literature
03:47it's not as vigorous as an
03:49acute reaction from infection,
03:51but is characterized by elevated
03:53levels of cytokines and acute phase
03:55reactants such as C reactive peptide.
03:57We've seen evidence of this in our own work.
04:01This was work done several years ago,
04:03and we joined forces with Ruth
04:06Montgomery's lab and this is data from.
04:08A primary human dendritic cells showing
04:11markedly elevated levels of pro inflammatory
04:13cytokine production at baseline,
04:15and these are levels that we
04:17never saw in primary dendritic
04:19cells from young individuals.
04:22And we think this chronic activation
04:24state contributed to an inability to
04:26further up regulate cytokine production.
04:29Appan encounter of a new
04:31pathogen or vac steam,
04:33so we model this by doing ex vivo
04:36toll like receptor stimulation.
04:38And pretty much across the board,
04:41you'll see decreased cytokine
04:42production is cohort of about 100
04:45young and older individuals following
04:46X people simulation and we have
04:49similar data for the TLR induced
04:51upregulation of costimulatory proteins.
04:53Now the mechanisms for this
04:55we're still investigating.
04:56I think it's multifactorial.
04:58One area that we think may play a
05:01role is the UP regulation in self.
05:04Some older adults of anti inflammatory
05:06cytokines and you see this.
05:08Shown in this slide.
05:10This is work from Sebastian
05:12Mohanty in the lab showing that.
05:14In monocytes evaluated following
05:16influenza vaccination that day,
05:17two 728 there's a substantial
05:19elevation and out ten production and
05:22anti-inflammatory cytokine in the mileage.
05:24The boss is ultimately focused
05:26on a negative regulator valve.
05:29Ten production, called Dust blonde.
05:31This is a map kinase phosphatase
05:33and showed that dust.
05:35One phosphorylation was downregulated
05:37in monocytes and older adults
05:39and is provided with potential
05:41mechanism to explain or at least
05:44a contributing factor to impaired.
05:46Innate immune responses in older individuals.
05:48Now we've been very fortunate.
05:50Go to be one center in the niht IDs
05:53Human Immunology Project Consortium,
05:56where one center of nine on a country
05:59where in our second cycle of funding
06:02were led by a David and Ruth as
06:05the peas and the purpose of the Hip
06:08See consortium is to evaluate or
06:11understand human immune responses,
06:13particularly under conditions of
06:14perturbation by infections or vaccines.
06:16And as an example,
06:18we recently published an assessment.
06:20I think the largest assessment of the
06:23effects of age on influenza vaccine response,
06:26evaluating signatures over a 5
06:28/ 5 consecutive vaccine seasons,
06:31and these were about 135 young
06:33and older adults stratified into
06:36individuals with very strong.
06:38Or weak or absent antibody responses
06:40to vaccination.
06:41One of the signatures that emerge
06:43from this work is a mitochondrial
06:46Biogenesis signature.
06:47Kind of linking metabolic function
06:49to immune response.
06:50We validated this at the protein
06:53level evaluating two nuclear encoded
06:55mitochondrial protein GHB 60 and a
06:57component of succinate dehydrogenase.
06:59If one looks at responders versus
07:02nonresponders that day seven,
07:04there were significant differences in
07:06the protein expression in young individuals.
07:09And more extensive differences in one
07:11looked at older vaccine responders
07:14compared to nonresponders at all
07:17time points post vaccination.
07:19However,
07:20there's a lot of heterogeneity
07:21in that we saw in this response,
07:24so this is work done in collaboration
07:27with Steve Kleinstein Slab,
07:28where I think it's complex and the reasons.
07:32Euro excellent or poor responder
07:34seem to largely differ or diverge
07:36dependent on whether you were
07:38older or in the young group.
07:40There was one area where
07:42there was some commonality.
07:43Is is this gene cluster C,
07:46which seemed to be shared between young and
07:48older adults and being downregulated today.
07:5128 post vaccine.
07:52It was enriched for a lot of immunological
07:54pathways and had three jeans.
07:57OK,
07:57McConnell again and the same dust one
07:59protein I mentioned or Gina mentioned.
08:02Earlier,
08:02along with another member of the family,
08:05this seemed to be shared in a
08:06kind of a regulatory capacity,
08:08and we think the source of this is at least
08:12in part T cells, be cause we saw
08:14a similar downregulation at 8:20.
08:16Eighteen purified T cell populations.
08:18So we finish by briefly discussing
08:21the current approaches for
08:22augmenting and responses in older
08:25adults for influenza vaccine.
08:27The high dose vaccines available.
08:29This is essentially preparation is
08:31four times the dose of hemagglutinin
08:34is in the standard dose vaccine.
08:37There is now a quadrivalent
08:39preparation that is in use.
08:41This was the original phase three
08:44trial led by Kip Talbot at Vanderbilt,
08:47then rolled over 30,000 individuals and
08:50found a modest relative reduction of
08:53about 24% in laboratory confirmed influenza,
08:55and this is all evaluating older individuals.
08:58Another approach has been to
09:01use a vaccine edge events.
09:03The other approved influenza
09:05vaccine preparation in the US for.
09:07Older adults is standard dose vaccine.
09:10It's aggravated with Emma 59.
09:12This is an agile meant as a squealing
09:15emotion that perhaps enhances antigen
09:17transport engine presentation.
09:19There's pretty good data for
09:22enhanced antibody responses in older
09:24adults compared to standard oh,
09:26Son,
09:26Edgerton vaccine and the hint in
09:29some studies that there may even be
09:32a more broadly based immune response
09:34in terms of antibody production to
09:37heterologous influenza vaccine strains.
09:39When using the agitated.
09:41Compared to an agent in vaccine,
09:44I should also comment on the management
09:47using the varicella zoster subunit vaccine.
09:50The SONB edge event used a
09:52combination of lipid,
09:54a tiller four agonist combined
09:56with US opponent glycoside,
09:58and there's really quite impressive
10:00vaccine efficacy that does not seem
10:03to be substantially age dependent,
10:05with almost essentially equivalent
10:07efficacy and individuals over age
10:1080 as compared to those in your 50s.
10:13And there's a number of vents
10:15are relatively small.
10:16Also,
10:16efficacy in the prevention
10:18of postherpetic neuralgia.
10:19So I think there's a promise.
10:21Therefore the use of agents to try
10:23to overcome the limitations of age
10:25in vaccines and a closeout mentioned
10:27something that's in the pipeline,
10:29somewhat surprising,
10:30and we can talk about it.
10:32The use of M Tor inhibitors for
10:35augmenting immune responses,
10:36as many of you know, mtor,
10:38in addition in terms of low dose rapamycin,
10:41has been used in animal.
10:43Model systems mooring systems to
10:45increase lifespan it probably does is
10:48by mimicking effects of caloric restriction,
10:51but this is work from restore Bio
10:54and Joan Mannix Group that have
10:57used two inhibitors of 1 downstream
11:00pathway event or torque one to
11:03show in all older individuals that
11:05use of both of these inhibitors
11:08resulted in increased antibody
11:09responses following in Saint BENS
11:12influenza vaccination and also.
11:14Surprisingly,
11:15six week course of these inhibitors
11:16resulted in a significant decrease
11:18in restaurant tract infections
11:20observed over one year period.
11:22So someone paradox too unsurprising
11:24to think of the biology of
11:26what mtor inhibition is doing,
11:28but it's something I think to
11:30keep in mind for the future.
11:32And with that,
11:33I'll thank all of our great
11:35collaborators at Yale.
11:36Many of which I mentioned.
11:38Also like to mention our long-term
11:40collaboration with the Claude
11:41Pepper Center at Yale, and wanted to
11:43thank everyone for your attention.
11:45And thank you for inviting me.