SARS-CoV-2 mRNA-1273 Vaccine in Older Adults

[Tom.G]

In the New England Journal of Medicine:

https://www.nejm.org/doi/full/10.1056/NEJMoa2028436 (also has links to supporting documentation)
https://www.nejm.org/doi/pdf/10.1056/NEJMoa2028436?articleTools=true

A stage 1 trial with 40 volunteers.
"After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells."

"
Conclusions
In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461. opens in new tab.)

http://clinicaltrials.gov/show/NCT04283461 (added in edit)

 

[jim mcnamara]

Note the endpoint is 394 days. If Phase III goes really well, they may stop early because of ethical concerns. It is considered to be not ethical to delay a therapy/vaccine that works really well.

In practical terms, this means an approved vaccine in ~April 2021. At the latest, and if it goes well.

The logistics of manufacture, distribution will add more time. Public resistance/denial problems will likely cause a continued pathogen presence in local populations long after that. The Oregon measles outbreak was a result of this resistance, for example.

Which means that Covid-19 may become like influenza, residual, in the sense that we have an influenza outbreak in North America every year. And of course, the longer the infections persist, even at a low level, the more likely mutations become.

Very like the flu. But. The flu virus occurs in multiple species, the chain of contagion:

Mallards(wild ducks) -> domestic pigs-> humans

so there are lots of infections that can mutate in the wild (non-human component). Onene reason why there are 4 primary strains of flu circulating at one time. With variants. In part, this is why vaccine is "quadrivalent" - four flavors.

Fortunately some strains are not associated with pandemics, which gives the vaccine developers a huge break.
[comment]
Otherwise we would have a dodecavalent serum?
[/comment]
Exact details -- See:
https://www.uabmedicine.org/-/flu-strains-explained-and-how-the-vaccine-works

List of the stuff in our current quadrivalent serum for the US:
https://www.cdc.gov/flu/prevent/quadrivalent.htm

 

[atyy]

Note the endpoint is 394 days. If Phase III goes really well, they may stop early because of ethical concerns. It is considered to be not ethical to delay a therapy/vaccine that works really well.

One argument for not stopping too early is that even if it is established the vaccine does give people immunity, the Phase III trial must still be large enough to catch rare adverse effects.

 

[jim mcnamara]

@atyy Yes. Think swine flu, and Guillain-Barre Syndrome. But there are a lot more concerns - efficacy, persistence, etc. It is a large population RCT, where they try to control for lots of confounding circumstances.

https://www.mayoclinic.org/diseases-conditions/guillain-barre-syndrome/symptoms-causes/syc-20362793

 

[Ygggdrasil]

Note the endpoint is 394 days. If Phase III goes really well, they may stop early because of ethical concerns. It is considered to be not ethical to delay a therapy/vaccine that works really well.

In practical terms, this means an approved vaccine in ~April 2021.

Moderna and other vaccine manufactures have released the protocols for their clinical trials. Instead of a fixed time endpoint, the vaccine manufactures have endpoints based on the total number of individuals in the trial who contract the coronavirus:

The panel, called a data-safety monitoring board, will perform its first analysis of Moderna’s efficacy data once 53 cases of Covid-19 have been diagnosed. Pfizer’s first analysis will be done after 32 cases.

The board could recommend stopping the Moderna trial after 53 cases if it was found to be 74 percent effective. In the case of Pfizer, the effectiveness would need to be better than about 77 percent.

Moderna has two more analysis points; Pfizer has four.

[...]

If the data are not conclusive, the panel would look again after there had been a total of 106 cases. If there were still no answer, the next and final analysis would occur after 151 people had contracted Covid.

How long it takes to reach any of those case counts depends on the trajectory of the pandemic and how likely participants are to be exposed to the virus.

Whether or not the vaccine is effective, the participants’ health will be monitored for two years after the second shot, the plan stated.

https://www.nytimes.com/2020/09/17/health/covid-moderna-vaccine.html

Thus, the trial has set certain points that they will look at the data, calculate the efficacy and set benchmarks of efficacy at which they would stop the trial.

Note that the point at which a vaccine gets approved is not the point at which it will become widely available, as a lot more need to happen after the clinical trial to manufacture and distribute the vaccine.

 

[jim mcnamara]

@Ygggdrasil
I got 394 from the registration listing at https://clinicaltrials.gov, I believe. I must have made a mistake. Thanks.

 

[Ygggdrasil]

@Ygggdrasil
I got 394 from the registration listing at https://clinicaltrials.gov, I believe. I must have made a mistake. Thanks.

The 394 day length listed on the clinical trials website is most likely related to followup on the people receiving the vaccine to look for long term persistence of immunity rather than and endpoint to evaluate efficacy.

 

[Laroxe]

Its worth remembering that regardless of when a vaccine is approved, particularly with the number in the system, there will be a period of enhanced monitoring, its not like information gathering will stop. The first problem is reaching the stage that we have sufficient data on effectiveness and safety to start using a vaccine, but then we need to identify the best and this might vary with different groups. Unfortunately there will always be some issues that we will have to wait to get the answer, persistence being a good example. There is another potential issue in the use of viral vectors if the vaccine needs repeated booster doses, we will develop antibodies to the vectors and that will effect the vaccines ability to do its job. We might be talking about vaccines for years and I expect we will see rapid changes in recommended vaccines and schedules during this period.