Saturday, April 06, 2019

C.I.D.: Influenza A Reinfection in Sequential Human Challenge

Credit NIAID


We've a fascinating study this morning published in Clinical Infectious Diseases which could have big implications for the development of a `universal' flu vaccine.
Adding additional gravitas to its unexpected findings, this study was conducted by researchers at the NIH and NIAID, and among the authors are two researchers frequently featured in this blog; David M. Morens, MD & Jeffery K. Taubenberger MD, PhD.
Although we know that the effectiveness of influenza vaccines can wane over time, it has been widely believed that once you are naturally infected with a specific influenza virus, you will carry lifelong - or at least long-lasting - immunity to that specific virus.

This `acquired immunity' is also expected to extend to antigenically similar viruses, although things get much murkier once even minor changes to the virus begin to accrue.
And we've seen evidence that this is true, at least on a population level.
In 1977, influenza H1N1 mysteriously reappeared on the world stage after an absence of 20 years. Since it was almost identical to a mid-1950's strain, many believe it may have accidentally `escaped' from the freezer of a Russian or Chinese research lab.
The upshot was, those born before 1957 - when this virus last circulated in the general population - were less affected by this virus, but kids and young adults born later were hit pretty hard. 
In the years that followed, H1N1 picked up enough antigenic changes to affect a wider cross section of the community, but when the 2009 H1N1 pandemic emerged - which was similar to an H1N1 circulating in the 1950s - once again those born before the late 1950s fared better than than those born later.
Despite a basic understanding of the human immune system, we are still miles away from understanding it completely.  A reality which is driven home by the surprising findings of today's study.
While I encourage you to download and read the full PDF, in a nutshell, researchers exposed a small group of healthy volunteers to a specific H1N1 virus, and recorded their subsequent infections and immune responses.
A year later, they repeated this virus challenge on the same group (n=7) with the same virus, expecting their residual immunity would protect them, but found instead that at least 3 - and possibly 5 - of the 7 were reinfected with the exact same virus.
While the cohort was small, and this research needs to be replicated on a much larger scale, its findings could have serious implications for flu vaccine research going forward.

The abstract, and a snippet from the study's conclusion, follow. 
Influenza A Reinfection in Sequential Human Challenge: Implications for Protective Immunity and “Universal” Vaccine Development
Matthew J Memoli, MD, MS Alison Han, MD, MS Kathie-Anne Walters, PhD Lindsay Czajkowski, NP-C Susan Reed, BS Rani Athota, PhD Luz Angela Rosas, MS Adriana Cervantes-Medina, BS Jae-Keun Park, DVM, PhD David M Morens, MD ... Show more

Clinical Infectious Diseases, ciz281,
06 April 2019

Identification of correlates of protection against human influenza A virus infection is important in development of broadly protective (“universal”) influenza vaccines. Certain assumptions underlie current vaccine developmental strategies including that infection with a particular influenza A virus should offer long term or lifelong protection against that strain, preventing reinfection. In this study we report observations made when 7 volunteers participated in sequential influenza challenge studies where they were challenged intranasally using the identical influenza A(H1N1)pdm09 virus approximately 1 year apart. We evaluate and describe the outcomes of these seven re-challenge participants and discuss what these results may suggest about correlates of protection and development of more broadly protective influenza vaccines.
Seven participants were enrolled in two viral challenge studies at 7.5 to 18.5 month intervals. Both challenge studies used the identical lot of influenza A (H1N1)pdm09 virus administered intranasally. We evaluated pre- and post-challenge HAI, NAI, and stalk antibody titers, peripheral blood leukocyte (PBL) host gene expression response profiles, daily viral detection via nasal wash, and clinical signs and symptoms.

At least 3 of 7 participants demonstrated confirmed laboratory evidence of sequential infection with 5 of 7 demonstrating clinical evidence.

The data presented in this report demonstrate that sequential infection with the identical influenza A virus can occur and suggest it may not be rare. These data raise questions about immune memory responses in an acute superficial respiratory mucosal infection and their implications in development of broadly protective influenza vaccines. Further investigation of these observations is warranted.
Sequential challenge performed with an identical influenza A virus in a small set of participants demonstrated that reinfection with the same virus can occur, in association with a diversity of susceptibility, illnesses, and immune responses. There were no obvious correlates of protection against reinfection, but many more individuals would need to be sequentially challenged to determine if such correlates exist.

The data presented here raise questions that must be investigated further as they could impact the development of broadly protective or universal vaccines. If infection following a high-dose viral challenge does not raise fully-protective homotypic immunity, can we expect vaccines to be made that will do so, let alone provide heterologous protection? Moreover, the individuality of outcomes observed in this small set of healthy volunteers is likely to be amplified greatly when vaccinating populations at large.
Identifying additional correlates of protection will be a critical first step, including evaluation of mucosal immunity mediated by secretory IgG and IgA, cellular immunity, and other effectors.
It is also possible that unknown genetic variations among the participants may also account for varied responses described here. It is likely that strategies may need to be employed that target multiple viral antigens to produce new generations of influenza vaccines that induce strong and durable protection. Clearly much more needs to be learned protection from infection and illness.
       (Continue . . . )

One of the things that influenza research has taught us is that nothing is ever as simple as it appears.  And that goes double for the human immune system. 

The most obvious concern is over how these findings might impact the development of a `universal' flu vaccine, which has been the Holy Grail of flu research for decades.

While a `universal' vaccine is often fancifully described in the popular press as being a `one time (or every few years) shot' that would convey nearly full protection against all flu subtypes, the immediate goal is for something considerably more realistic. 

Credit NIAID

While today's study doesn't negate the possibility of reaching this goal, it does suggest it may be a more difficult road than many have hoped (see J.I.D.: NIAID's Strategic Plan To Develop A Universal Flu Vaccine).