Rita Rubin, MA
JAMA. 2021;325(13):1241-1243. doi:10.1001/jama.2021.3370 March 17,
2021
Coronavirus
Variants and Vaccines
As
COVID-19 cases resulting from infection with SARS-CoV-2 variants accumulate in
the US and around the world, one question looms large:
How
well do the COVID-19 vaccines developed so far protect against these novel
coronavirus spinoffs?
“The
virus is telling us it’s going to throw out a lot of mutations,” infectious
disease specialist Jesse Goodman, MD, MPH, who, as then-chief scientist at the
US Food and Drug Administration (FDA), led the agency’s response to the H1N1
influenza A pandemic, said in an interview. “Even if we don’t have a critical
situation right at the moment…there’s a realistic possibility that variants
will continue to evolve that have potential to avoid vaccine immunity.”
That’s
to be expected, Anthony Fauci, MD, director of the National Institute of
Allergy and Infectious Diseases (NIAID), told JAMA Editor in
Chief Howard Bauchner, MD, in a February 3 podcast. Regardless of the platform on which
the vaccine is based, Fauci said, “you still have a fixed immunogen and a virus
that’s changing. Sooner or later, you’re going to get a mutant that evades
that.”
One
reason SARS-CoV-2 is throwing out variants and will continue to do so is
because relatively few people globally have been vaccinated, Norman Baylor,
PhD, a former director of the FDA’s Office of Vaccines Research and Review,
noted in an interview. “This virus is like, ‘Yep, I’ve got plenty of people I
can infect, and the more I replicate, the more I can mutate,’” Baylor said.
Some
scientists have used the term vaccine
resistance to describe the reduced efficacy of COVID-19
vaccines against some variants. But that confuses matters by suggesting
vaccines are analogous to antibiotics, University of Washington biologist Carl
Bergstrom, PhD, who studies evolution and medicine, said in an interview. “The
key point for me is that in antibiotic resistance, the changes happen in people
who are on antibiotics,” he said, while antigenic escape by SARS-CoV-2 occurs
in people who haven’t been vaccinated.
When
viruses replicate, Penn State biologist David Kennedy, PhD, explained in an
interview, the cycle is like a classic childhood game. “Viruses copying
themselves, it’s almost like a game of telephone,” said Kennedy, who studies
pathogen evolution. “They repeat what they thought they heard, so they make
mistakes all the time.”
Despite
those many mistakes, Kennedy noted, he’s unaware of any vaccines against viral
diseases other than seasonal flu that have had to be updated because of changes
in the virus. Hepatitis B virus developed “vaccine
escape mutations,” but they posed no health risks, he said.
Good
Enough?
Current
COVID-19 vaccines are based on the SARS-CoV-2 spike protein, which the virus
uses to bind to and infect host cells, of the original Wuhan-hu-1. But the
emerging “variants of concern”—deemed so because they appear to be more
transmissible or deadlier than the wild-type SARS-CoV-2—contain mutations in the spike protein,
spurring vaccine efficacy concerns.
Trials
of the Novavax, Janssen/Johnson
& Johnson, and AstraZeneca vaccines in South Africa, where the
B.1.351 variant of concern represents virtually all of the circulating
SARS-CoV-2, seemed to justify those concerns. The South Africa trials found
lower vaccine efficacy compared with trials in other countries where B.1.351
wasn’t dominant.
The
pivotal trials of the Pfizer-BioNTech and Moderna vaccines, the first 2 authorized
by the FDA, were conducted mainly in the US before any cases of infection by
B.1.351 or other variants of concern had been detected in the country.
Much
of the current data on the messenger RNA (mRNA) vaccines’ efficacy against
SARS-CoV-2 variants has come from laboratory studies in which researchers
exposed serum samples from immunized individuals to genetically engineered
versions of concerning variants and then measured neutralizing antibody titers.
Such studies repeatedly have shown the vaccines elicit lower levels of
neutralizing antibodies against SARS-CoV-2 variants than against older, more
common isolates.
For
example, in a February 17 letter to the editor in The New
England Journal of Medicine, scientists described testing serum samples
from individuals immunized with 2 doses of the Pfizer-BioNTech vaccine against recombinant
viruses containing some or all of the spike protein mutations found in the
B.1.351 variant. Neutralization of B.1.351 was approximately two-thirds lower
than that of USA-WA1/2020, an early SARS-CoV-2 isolate.
In
another letter published the same day,
researchers reported measuring neutralizing antibody activity in serum samples
from participants in the phase 1 trial of the Moderna COVID-19 vaccine. One
week after the participants received the second dose, neutralizing antibody
titers induced by a recombinant virus bearing the B.1.351 spike protein were
6-fold lower than those induced by a recombinant virus bearing the original
Wuhan-Hu-1 spike protein.
However,
that still might be sufficient to protect against COVID-19, or at least severe
COVID-19.
“Fortunately,
neutralization titers induced by vaccination are high, and even with a 6-fold
decrease, serum can still effectively neutralize the virus,” Fauci and 2 NIAID
colleagues wrote in a JAMA editorial posted
February 11. And, they noted, lower vaccine efficacy in the South African
clinical trials could be related to geographic or population differences.
Although
serum antibody levels correlate well with protection for many infectious
diseases, protective levels haven’t yet been determined for SARS-CoV-2. They
may never be established, Baylor said. “With some organisms, it’s very
difficult to pinpoint exactly what level of [antibody] response is needed,” he
said, citing the bacterium that causes pertussis as
one such microbe.
In
addition to neutralizing antibodies, mRNA vaccines also induce virus-specific
helper T cells and cytotoxic T cells that might help protect against infection,
Paul Offit, MD, director of the Children’s Hospital of Philadelphia’s Vaccine
Education Center, and John Moore, PhD, a microbiologist and immunologist at
Weill Medical College of Cornell University, noted in a JAMA viewpoint published recently.
Assays
of serum samples from participants in the phase 1 and phase 3 trials of Johnson
& Johnson’s adenovirus-based vaccine, which the FDA authorized for emergency use on
February 27, suggest that neutralization correlates with protection but
probably is not the only biomarker that does, Johan Van Hoof, MD, who oversees
vaccine research and development at Janssen, a Johnson & Johnson
subsidiary, said February 26 during an FDA advisory committee meeting.
Experiments
vs Experience
Without
immune correlates of protection, only real-world experience can provide answers
about COVID-19 vaccines’ efficacy against illness and death from SARS-CoV-2
variants.
“For
right now, you know that a line is crossed if you see people fully immunized
with the vaccines [who], nonetheless, when infected with the variants, are
being hospitalized,” Offit said at a February 4 COVID-19 Vaccine
Analysis Team press briefing.
At
first glance, findings from a phase 2 trial of the Oxford-AstraZeneca vaccine
in South Africa seemed quite discouraging, spurring that country to suspend its planned rollout of the
vaccine. The trial found that the vaccine did not protect against mild to
moderate COVID-19 caused by the B.1.351 variant. The findings,
posted February 12, had not been peer reviewed.
However,
“the study was not really designed to determine whether the vaccine could
protect against severe COVID or not,” principal investigator Shabir Madhi,
MBBCH, PhD, a vaccinologist at the University of the Witwatersrand,
Johannesburg, and cofounder and codirector of the African Leadership Initiative
for Vaccinology Expertise, said in a February 7 briefing about
the results. Participants, who numbered only about 2000, were young—average age
31 years—and healthy, so their risk of severe disease was low, vaccinated or
not, explained Madhi, who also led Novavax’s vaccine trial in South Africa.
Novavax and Janssen conducted larger trials in South
Africa than Oxford and AstraZeneca. Although both of their vaccines had lower
efficacy rates in South Africa than in trials in other countries, vaccinated
participants who received the Janssen vaccine were still less likely to require
hospitalization for COVID-19 than those who received placebo shots, and Madhi
recently told Nature he expected that to be the
case with the Novavax vaccine as well.
Goodman
concurred. “It’s consistent with how the immune system works,” he said,
explaining that although protection against B.1.351 might be incomplete,
vaccines could still protect against severe COVID-19. In regard to the
Oxford-AstraZeneca vaccine, he said, “my guess is it will be like the other
vaccines and have some effect” against B.1.351.
As
Baylor, a consultant on vaccines for the World Health Organization, noted, “One
of the biggest things you want to do in a pandemic is keep people from dying
and keep them out of the hospital.”
That
appears to be happening.
COVID-19
cases and hospitalizations started to decline in mid-January in Israel, which leads the world in percentage of
the population vaccinated. Larger and earlier decreases occurred among older
individuals, who were a top priority for vaccination, according to an article posted
February 9 that had not been peer reviewed. In the week before the study was
posted, COVID-19–related hospitalizations declined by 36% and 29% fewer
patients were severely ill with COVID-19 than 3 weeks earlier. The B.1.1.7
variant, first identified in the UK, is now the dominant SARS-CoV-2 variant in
Israel as well as in the UK. That variant doesn’t appear to reduce neutralizing
antibodies to the same extent as B.1.351.
Similarly
encouraging UK data, although not peer reviewed, were posted in February.
In
Scotland, researchers estimated that Pfizer-BioNTech’s vaccine
was up to 85% effective and Oxford-AstraZeneca’s vaccine up to 94% effective in
preventing COVID-19–related hospitalizations 28 to 34 days after a single
dose—the UK policy is to provide the second dose 12 weeks later.
A
Public Health England (PHE) report on immunization with the
Oxford-AstraZeneca or Pfizer-BioNTech vaccine noted that “early data suggest
that any cases that do occur in older vaccinated people are around half as
likely to lead to hospitalisation and/or death.” The data came from those
vaccinated only 14 days earlier; lower rates of hospitalization and death would
likely be seen in people vaccinated more than 3 or 4 weeks earlier, the report
noted.
Stopping
the Spread
The
US Centers for Disease Control and Prevention advises that even after they’re fully
vaccinated, people should continue to mask up and socially distance in public
places in part because they could still unknowingly become infected and,
although asymptomatic, transmit SARS-CoV-2 to people who haven’t yet received
their shots.
Transmission
by infected asymptomatic vaccinees could provide an opportunity for more
virulent variants to spread, Kennedy suggested in a 2015 article.
The article described an experiment with a herpes virus that causes Marek disease in chickens. Vaccines
against Marek disease are described as “leaky” because, although they protect
chickens from getting sick, they don’t prevent them from becoming infected and
transmitting the virus to unvaccinated chickens. That allows the most virulent
strains that normally would die along with an infected chicken to survive and
infect and kill unvaccinated chickens, the experiment found.
Fortunately,
as the article notes, nearly all vaccines used in humans prevent asymptomatic
infection and spread.
“In
general, vaccines that are effective in reducing infections do have major impacts
on reducing transmission,” said Goodman, director of Georgetown University’s
Center on Medical Product Access, Safety and Stewardship. “It is probable that
these vaccines will reduce transmission.”
Mounting
evidence supports that notion. In a study of
UK health care workers immunized with the Pfizer-BioNTech vaccine, participants
underwent biweekly polymerase chain reaction testing and twice weekly rapid
antigen testing to help investigators determine rates of asymptomatic and
symptomatic infections.
The
study, posted February 22 but not peer reviewed, found a 70% reduction in both
types of infection 21 days after participants received their first dose and an
85% reduction a week after receiving their second dose. “Overall, we’re seeing
a really strong effect to reducing any infection—asymptomatic and symptomatic,”
coauthor Susan Hopkins, MD, PHE strategic response director, said at a press
conference. In March, Pfizer and BioNTech announced that non–peer-reviewed data
from Israel showed their vaccine was 94% effective against asymptomatic
SARS-CoV-2 infection.
Next
Steps
Whether
COVID-19 will join influenza as an infectious disease for which annual
vaccination is required isn’t yet known. Although they’re both RNA viruses,
“the backdrop is so different,” Baylor said. “We are in a pandemic. We didn’t
have a vaccine. This [mRNA vaccines] is new technology.”
Short
of developing a universal vaccine that protects against most SARS-CoV-2
variants, “we need to be prepared to make alterations in the existing
[COVID-19] vaccines to deal with [variants] that emerge,” Goodman said.
Out
of what they call an abundance of caution, manufacturers say they’re developing
strategies to deal with the possibility of a variant that escapes coverage by
first-generation vaccines.
At
the February 26 FDA advisory committee meeting, Van Hoof said Janssen plans to
launch a phase 1 trial of a SARS-CoV-2 variants vaccine by this summer.
Pfizer
and BioNTech announced February 25 that they had begun
evaluating the safety and immunogenicity of a third dose of their vaccine to
see whether it would boost immunity to SARS-CoV-2 variants. In addition, the
companies said they are discussing with regulatory agencies, including the FDA,
a clinical study to evaluate a modified vaccine based on the B.1.351 variant.
“The companies are hoping to pursue the validation of future modified mRNA
vaccines with a regulatory pathway similar to what is currently in place for
flu vaccines,” according to a press release.
Moderna announced February 24 that it had shipped
a booster vaccine candidate based on B.1.351 to the NIAID for a phase 1 trial.
And Novavax, whose first-generation vaccine hasn’t been authorized yet in the
US, announced January 28 it was working on developing a booster, a combination
bivalent vaccine, or both to protect against variants. The company said it
expected to begin clinical trials in the second quarter of 2021.
Modifying
vaccines to target variants isn’t difficult. For example, with
Pfizer-BioNTech’s and Moderna’s mRNA vaccines, “it’s very convenient, because,
basically, all you do is change a computer program and the synthetic for the
synthesizing portion of this and you can change the vaccine,” Peter Marks, MD,
PhD, director of the FDA’s Center for Biologics Evaluation and Research, which
regulates vaccines, said during a January 29 American Medical Association
(AMA) webinar. “But the question is, what do we need
from the FDA perspective to feel comfortable having that deployed.”
On
February 22, the FDA updated its nonbinding guidance for vaccine manufacturers to
include information about what the agency would like to see when evaluating
vaccines that have been modified to address emerging SARS-CoV-2 variants.
The
updated guidance advises manufacturers to conduct studies comparing
neutralizing antibody responses to SARS-CoV-2 induced by the modified vaccine
with those induced by the prototype vaccine. One such study should use serum
samples from people who hadn’t been previously vaccinated or infected with
SARS-CoV-2, while another study would use serum samples from people previously
vaccinated with a prototype vaccine who then received an experimental booster
against variants of concern.
The
Hard Part
Modifying
COVID-19 vaccines would probably be the most straightforward step in dealing
with SARS-CoV-2 variants. “For vaccines and biologics, it’s the manufacturing
process that defines the product, and the manufacturing process isn’t
changing,” Baylor explained.
More
challenging will be deciding when and how to deploy COVID-19 vaccines 2.0. The
influenza model, in which surveillance during the Southern Hemisphere’s flu
season identifies the circulating strains to target with vaccines in the
Northern Hemisphere’s coming flu season, doesn’t work for SARS-CoV-2, Baylor
noted.
“The
challenge for COVID is what variant do you pick” when modifying a vaccine, he
said. “How often does it change?”
Once
that’s decided, would people who’ve already received the original COVID-19
vaccine get a booster shot to protect against variants of concern while
vaccine-naive individuals receive the original vaccine and the booster rolled
into one? “Do we have the capacity to make both?” Baylor asked.
Plus,
the need to deploy vaccines or boosters targeting new variants would complicate
the already rocky rollout of COVID-19 vaccines, in part due to inexperience in
vaccinating US adults en masse.
“How
do we deploy this?” Baylor said of next-generation COVID-19 vaccines. “When do
we pull the trigger to actually do this?”
March 18, 2021
Herd Immunity, Vaccination and Non-Pharmacological Interventions
KS Lam |
The critical variables for calculating herd immunity threshold
include reproduction number and efficacy against transmission. The virus has
been mutating since it was identified a year ago. There are varying degrees of
uncertainties involved in these metrics. CDC in the Morbidity and Mortality
Weekly Report reported that B.1.1.7 is assumed to be 50% more transmissible
than current variants [1]. The current R0 is about 1. Using the current
baseline R0 of 1, the R0 for the new variants should not be more than 1.5 as
CDC is deploying "rigorous implementation of public health strategies to
reduce transmission and lessen thepotential impact of B.1.1.7,
buying critical time to increase vaccination coverage". Therefore, the
theoretical herd immunity threshold is estimated at 30%.
Estimated efficacy for preventing transmission is 74% based on a controlled
clinical trial carried out by Janssen [2]. This efficacy should be much lesser
due to infrequent testing for asymptomatic cases. Real world studies also
suggest the vaccines will at least partly reduce transmission [3, 4].
Even though the impact on reducing transmission is less than ideal, let say
50%, the percentage of the population that must be vaccinated is just about
60%. This vaccine coverage is a shorter path to reach out to the 47% of the
public who said they wanted to get the vaccine as soon as possible [5]. So far
12% of the population was already fully vaccinated [6].
This best case vaccination scenario provides a strong rationale for continued
mask wearing, physical distancing, frequent antigen testing and contact
tracing. These mitigation measures are used to leverage on herd immunity to
transition toward normalcy progressively amid emerging more-infectious dominant
variants.
References:
1. http://dx.doi.org/10.15585/mmwr.mm7003e2
2. https://www.fda.gov/media/146217/download#page=35
3. https://www.nejm.org/doi/full/10.1056/NEJMoa2101765
4. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab229/6167855
5. https://jamanetwork.com/channels/health-forum/fullarticle/2776458
6. https://covid.cdc.gov/covid-data-tracker/#vaccinations
CONFLICT OF INTEREST: None Reported
March 29, 2021
Vaccine Passes
Jay Ja, Business | Harvard
New York rolled out Excelsior Pass recently. It has promise. For
other countries to follow. Banning smoking in public establishments is similar.
No pass, no public access. The B117 variant is more lethal and more
transmissible. We will not win without the world getting vaccinated. All
countries, rich and poor.
CONFLICT OF INTEREST: None Reported
April 7, 2021
Vaccinated Asymptomatic Carriers
Dr Mubarak M Khan, MBBS, DLO, DNB (ENT) | Sushrut ENT
Hospital & Dr Khan’s Research Centre, Talegaon Dabhade, Pune, india
As the vaccination drive is on worldwide in full swing for
lowering the speed of coronavirus spread and to attain herd immunity, important
questions arise and finding answers must be part of further research:
1. Do vaccinated populations become asymptomatic carriers for Covid 19 and
SARS-CoV-2 variants?
2. Do asymptomatic carriers continue spreading SARS-CoV-2 to unvaccinated
populations?
3. What happens to vaccinated populations when they get infected with
SARS-CoV-2 again? Are there distinct pathophysiologic changes?
4. Although Covid-19 vaccines seems to help prevent severe disease, is there is
increased risk of hyperimmunity or blood clots or any other autoimmuneresponses in people who are vaccinated and get infected with Covid
again?
5. Does reinfection in vaccinated people increase neutralising antibodies?? If
so for how many months?
Many more questions will arise which must be given priority while continuing
mass vaccination. As all vaccines have been rapidly developed and used in a
very short period, continuous monitoring and strict follow up of all vaccinated
populations is imperative.
Regards
Dr Mubarak Khan
Dr Sapna parab
Consultant and Director
Sushrut ENT Hospital & Dr khan’s Research centre, pune
CONFLICT OF INTEREST: None Reported
April 8, 2021 ACE2
and Neutralising Antibodies
Camilo Colaco, PhD | Independent Scientist
SARS-CoV2 binds to the ACE2 receptor on cells. The domain of the
Spike protein that mediates this binding is the RBD domain and most of the
neutralising antibodies measured in the efficacy assays used are primarily
against this domain and hence 'neutralise' the virus. Is it likely that
'escape' of variants from binding by neutralising antibody reflect
modifications of the RBD domain and thus the ability of the viral variant to
bind ACE2? If this affects cellular infection by SARS-CoV2, what does this mean
for the clinical course of CoVID19?
CONFLICT OF INTEREST: None Reported
April 15, 2021 Coordination
Needed
Eugene Mannacio | M.I.T.
As the article clearly states, the true effectiveness of any of
the vaccines against variants can only be determined with real world infection
data. At this time millions of people have been vaccinated and some of the
variants appear to be quite prevalent, which makes exposure to those variants
by vaccinated individuals highly likely. So it should be possible to identify
how many so-called "breakthrough" cases of infection in those
individual there are and by which variants. None of the vaccines has been shown
to be 100% effective in the prevention of all levels of infection so,
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