What does Vaccine Efficacy Really Mean and How Might it Change?

Summary:

The "efficacy" of a vaccine(VE) is a convenient number, but it's often provided without vital context that would ensure it is interpreted correctly. There are different kinds of efficacy that matter, and the numbers reported are often at peak levels following vaccination. It is in the commercial, professional, and political interest of drugmakers, the media, virologists, and policymakers to emphasize the highest number to demonstrate the power of the vaccines.

The 3 primary outcomes that vaccination is intended to prevent are severe disease, infection, and transmission. The number for severe disease is likely to be highest, while the number for transmission is likely to be lowest. This is because different aspects of the immune response affect each.

There are 3 main takeaways: VE is usually reported in terms of prevention of severe disease, VE can change against infection and severe disease independently, and SARS-CoV-2 is likely to escape from today's vaccines sooner rather than later, but more slowly from hospitalization and death.

Critically, mutation occurs when infection and replication occur and accrues as transmission occurs, eventually being driven by natural selection to evolution. The VE against infection and transmission are most relevant to future VE in all categories.

Detailed findings:

It has been demonstrated that even recent vaccination against the SARS-CoV-2 S protein only reduces the risk of transmission from infected people by the older strains by 41% in a real-world setting with high infection risk. There are indications that the degree of reduction is much lower, perhaps negligible, in Delta, due mostly to the high viral load it induces. The viral load numbers underestimate the real-world reduction in transmission because they only focus on individuals who have been infected, and vaccines still reduce the odds of infection meaningfully. However, the increased sneezing compensates for this.

https://ncrc.jhsph.edu/research/vaccination-with-bnt162b2-reduces-transmission-of-sars-cov-2-to-household-contacts-in-israel/
https://www.cdc.gov/mmwr/volumes/70/wr/mm7031e2.htm

VE numbers change over time as the primary surge of antibodies from vaccination recedes and B-cells and T-cells take over and as the virus evolves into new strains.

T-cells are critical in prevention of severe COVID-19, while antibodies are more important for preventing infection and transmission. They target different parts of the virus, so a mutation that weakens a vaccine's efficacy against infection may not weaken its efficacy against severe disease, and vice-versa.

T-cells recognize a larger number of viral epitopes, around 35 in an average anti-S SARS-CoV-2 T-cell, making it harder to escape from their cytotoxic and immune orchestration abilities. Of these epitopes, 6 that are recognized by the average vaccine recipient have mutated on average in SARS-CoV-2, with progressively greater numbers in Alpha, Beta, and Gamma. T-cells also rely on clonal expansion, making them more durable protection than antibodies. The large number of recognized epitopes makes it harder for the virus to escape T-cells than antibodies, so protection against severe disease is easier to achieve.

https://www.nature.com/articles/s41467-021-25167-5

Disease is only caused by a pathogen to the extent that it helps viral survival and spread. Killing you is generally not a viral goal, as it's a murder-suicide. However, a high amount of pathogenicity can be accommodated if the increased spread from disease counterbalances accidentally killing the occasional host, so viruses can be inherently variably deadly, and the "ideal" amount of virulence depends on other viral-host factors.

Each globally dominant variant has been progressively more deadly than its progenitor, strongly indicating that SARS-CoV-2 benefits from being more virulent thus far, and that will be especially true in vaccinated people. There will be strong evolutionary pressure to become more severe in vaccinated people, most likely through interfering with T-cell responses with escape mutations and accessory protein evolution, and SARS-CoV-2 evolves remarkably fast.

https://www.medrxiv.org/content/10.1101/2021.07.05.21260050v3.full-text

Antibodies, by contrast, are more focused on the prevention of SARS-CoV-2 infection. They reduce the severity of disease, but not as much as T-cells. Higher antibody titers are found in severe infections than in mild infections, while lower T-cell numbers are found in severe infections than in mild infections.

https://www.nature.com/articles/s41467-020-20247-4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389156/

Real-world longitudinal data on disease outcome and antibody titers support this conclusion.

https://www.medrxiv.org/content/10.1101/2021.06.29.21259500v1.full-text
https://www.medrxiv.org/content/10.1101/2021.06.21.21258528v1.full-text#T2

Which epitopes are recognized by individual antibodies matters greatly. It is not known how many exactly how many SARS-CoV-2 epitopes are targeted by antibodies, while there are 1400+ distinct epitopes targeted by T-cells. Some can bind strongly to a virus but fail to neutralize it. Vaccine efficacy against infection will generally drop more quickly due to waning antibody numbers and antigenic drift.


A question potentially facing SARS-CoV-2 right now is whether it's more important to be more infectious or whether it's more important to be more virulent, as it can be a trade-off. However, it has demonstrated the ability to achieve each individually or simultaneously. Given how well the progeny of Delta spread in people, further evolution should be easy no matter how many people are vaccinated with today's vaccines.

With more people vaccinated or previously infected, the dominant trend should be towards increased immune escape more than increased infectivity. Complete escape from vaccines in general is unnecessary, but escape by strains from current vaccines is inevitable anyway because of fast evolution and low vaccine efficacy.

https://www.nature.com/articles/s41598-021-95025-3

Comments

Post a Comment

Popular posts from this blog

Dangerous Original Antigenic Sin Anticipated in SARS-CoV-2

Disclaimer : This is an opinion and a prediction that includes as many sources and the best logic possible. Do not base your personal health decisions on it. Plain Language Introduction SARS-CoV-2 is a novel virus with its closest relatives in bats, emerging in the human population at some point in late 2019. As a newly introduced pathogen, there was only one variant at first. Now we have thousands of strains that have been identified, with countless individual virus particles with countless mutations. The genetic diversity of SARS-CoV-2 is much greater than scientists thought it would be by this point in time. Recombination and Evolution That's because we failed to notice that SARS-CoV-2 relies heavily on recombination for evolution. With recombination, in a host that is infected with two strains of the virus, the virus can effectively create a child from two parent virions(a virion is a single virus) through a process called strand switching. When creating a new vi...
Read more

Do Vaccines Prevent COVID-19, or just Delay It?

Image
First, the good news: it looks like global Reff for SARS-CoV-2 is approaching 1 . However, what lies next? Do we see sharp case declines like India and Indonesia did after Delta passed, will we see a lingering high level of cases like South Africa , or something else entirely? Second, the bad news: it's unlikely to stay at or below 1 for long. That could always have been anticipated due to the high R0 and evolutionary rates of SARS-CoV-2 . https://origin-coronavirus.jhu.edu/data/new-cases Unlike India and Indonesia, heavily vaccinated countries like the UK are demonstrating protracted Delta waves, which raises independent questions about whether vaccination prevents cases or just delays them. The US is as well. Still, Reff is trending towards 1 here, albeit at a very high level of cases. We can expect it to hover there as it moves north with the changing seasons. A brand new letter to the editor in the NEJM depicts this perfectly. You will see that infection h...
Read more
Image
In support of my conclusions, observe that Mexico, Central America, and the north of South America are seeing healthy co-circulation of VOC's that are antigenically distant.  Delta is not stomping out these VOC's; it is at about 50% prevalence there, and has little representation in the rest of South America.  B.1.621, Kappa(B.1.617.1, which has a markedly different S protein than B.1.617.2), and P.1.x are growing steadily.  Mexico has just set a record for new weekly and monthly cases. Delta took over in the US much more quickly and thoroughly, probably because we had much lower prevalence of the other strains than they did at the beginning(B.1.621 emerged in Colombia) and more import from overseas, even though we're more vaccinated(Mexico is at 22% fully vaccinated).  We might expect even greater expansion of those strains here over time.  You can watch the relative percentage of sequenced strains since Delta's export by zooming the map and press...
Read more