Rather than a World Trade Organization (WTO) patent waiver, COVID vaccine equity requires improvements to manufacturing and distribution of vaccines in the Global South and compulsory licensing mechanisms, according to a statement by ALLEA, the European Federation of Academies of Sciences and Humanities.
They state that the low level of COVID vaccination in the Global South is ethically unacceptable and risks prolonging the pandemic. At the end of 2021, access to Covid-19 vaccines is still a priority. Only 5.9 % of people in low-income countries have received at least one dose (on 29 November 2021, compared with 0.3% on 14 April), with numbers in Africa remaining very low, save for Morocco. The patent waiver being discussed within the WTO since 2020 will not solve these vaccination bottlenecks in the short-term. For instance, the waiver as proposed by South Africa and India would in practice require unanimity between the 164 WTO Members to be adopted – to achieve this in practice would simply delay the waiver until after the pandemic.
Rather, measures should be undertaken to accelerate local manufacturing and distribution of vaccines in low- and middle-income countries (LMICs), ramp up investment in vaccination campaigns, and facilitate the compulsory licensing of patents and knowledge transfer.
In particular, the statement advocates for (i) practical measures that could accelerate the production, export, distribution, and administration of vaccines worldwide and ii) an international mechanism affording additional scrutiny of the manufacturing bottlenecks combined with new measures in the intellectual property (IP) framework such as flexibility for the compulsory licensing of patents.
According to the experts, the current co-sponsored waiver proposal at the WTO is “not well-tailored to the urgent vaccine problem” and needs additional national legislation to have any practical effect. A WTO waiver would only remove the obligation for WTO Member States to grant IP protection, but would not ensure that stakeholders can effectively benefit from the invention and related know-how.
“A waiver (in the sense of the co-sponsored proposal at the WTO) of IP protection, including of trade secrets, would never make this know how publicly accessible, but only remove the possibility for companies enjoying confidentiality protection to sue for trade secret infringement”, the experts argued.
Other IPR measures need to be considered instead, with the WTO waiver debate raising other IP fixes that are needed in the field of health. The WTO rules on compulsory licensing of health-related patents should be amended. Important adjustments to patents and trade secret protections should also be adopted by the EU, its Member States, and other countries. In particular, improved procedures and institutional design should help to streamline the process for compulsory licensing on pharmaceutical products, including vaccines.
With the COVID test positivity rate climbing above 30%, President Cyril Ramaphosa is widely expected to address the nation in the coming days. Health Minister Dr Joe Phaahla said on Friday that the National Coronavirus Command Council would be meeting on Tuesday or Wednesday to discuss new restrictions in the face of surging infections.
The main concern is centred around the large number of gatherings that will take place over the festive period: under Level 1 lockdown rules, gatherings of up to 750 individuals are permitted indoors. The Bureau for Economic Research issued a report saying that data so far indicates that there are fewer hospitalisations and less severe disease with the Omicron variant, in line with observations made since the start of the variant’s outbreak.
A partial ban on alcohol sales seems likely, according to a source cited by City Press: “He is considering proposing to the NCCC and cabinet a few adjustments, which include banning the sale of alcohol on weekends and public holidays until mid-January. Don’t be surprised when we have a family meeting before Thursday. He is serious about protecting the country.”
He initially had no plans to address the nation, sources said, but was motivated to change his view in light of the increasing rate of transmission.
Meanwhile, the UK appears set to scrap its controversial red list, which had been widely viewed as unfairly targeting South Africa. The red list amounted to a virtual travel ban, with travellers forced to pay £2285 (R48 400) per person for a ten day stay in often substandard quarantine accommodation. However, it will come too late for many people who have cancelled travel plans.
In a windfall for South Africans, the cost of PCR testing has been revised downward to R500 from R850 as of Sunday following a complaint lodged with the Council for Medical Schemes against private pathology laboratories, alleging the pricing for COVID PCR tests was unfairly inflated. Pricing for rapid antigen tests is said to be next on the list for the Competition Commission.
On Sunday, a technical glitch caused the National Health Laboratory Service to delay release of a large portion of test results. The glitch meant that initially 18 035 cases were released initially, which rose to over 37 000 after the correction.
The cause was put down to IT difficulties with various laboratories.
A report in Nature examines why Omicron was such a surprise, and how the possible evolutionary pathways available to SARS-CoV-2 shape future scenarios of the COVID pandemic.
Currently, Delta and its descendants still dominate worldwide, and they were expected to eventually outcompete the last holdouts. But Omicron has undermined those predictions. “A lot of us were expecting the next weird variant to be a child of Delta, and this is a bit of a wild card,” said Aris Katzourakis, a specialist in viral evolution at the University of Oxford, UK.
The Omicron surge in South Africa suggests that the new variant has a fitness advantage over Delta, said Tom Wenseleers, an evolutionary biologist and biostatistician at the Catholic University of Leuven in Belgium. Omicron has some of the mutations associated with Delta’s high infectivity – but if increased infectivity alone explained its rapid growth, it would mean an R0 (reproduction number) in the 30s, said Wenseleers. “That’s very implausible.”
At present, Omicron appears to have an R0 of 1.36, after its initial surge, based on a continually updated estimate by Louis Rossouw, head of research and analytics at Gen Re. Weneseelers and other researchers instead suspect that Omicron’s rise may be due to its re-infection and vaccine evasion ability.
If Omicron is spreading, in part, because of its ability to evade immunity, it fits in with theoretical predictions about how SARS-CoV-2 is likely to evolve, says Sarah Cobey, an evolutionary biologist at the University of Chicago in Illinois.
As SARS-CoV-2’s infectivity gains start to slow, the virus will maintain its fitness by overcoming immune responses, said Cobey. If mutation halved a vaccine’s transmission blocking ability, this could open up a vast number of hosts. It’s hard to imagine any future infectivity gains providing the same boost.
The evolutionary path towards immune evasion and away from infectivity gains, is common among established respiratory viruses such as influenza, said Adam Kucharski, a mathematical epidemiologist at the London School of Hygiene and Tropical Medicine. “The easiest way for the virus to cause new epidemics is to evade immunity over time. That’s similar to what we see with the seasonal coronaviruses.”
Analysis has shown a wealth of Spike protein mutations that weaken the potency of neutralising antibodies resulting from infection and vaccination. Variants like Beta that have such mutations, have degraded – but not destroyed – vaccine effectiveness particularly against severe disease.
Compared with other variants, Omicron contains many more of these mutations, particularly in the region of spike that recognises host cells. Preliminary analysis from evolutionary biologist Jesse Bloom suggests that these mutations might render some portions of Spike unrecognisable to the antibodies raised by vaccines and previous infection with other strains. But lab experiments and epidemiological studies will be needed to fully appreciate the effects of these mutations.
Evolutionary costs and benefits Evolving to evade immune responses such as antibodies could also carry some evolutionary costs. A Spike mutation that dodges antibodies might reduce the virus’s ability to recognise and bind to host cells. The receptor-binding region of Spike, the main target for neutralising antibodies. is relatively small, explained Jason McLellan, a structural biologist at the University of Texas at Austin. Thus, the region might tolerate only small changes if it retains its main function of attaching itself to host cells’ ACE2 receptors.
Repeat exposures to different Spike versions, through infection with different virus strains, vaccine updates or both, eventually might build up a wall of immunity that SARS-CoV-2 will have difficulty overcoming. Mutations that overcome some individuals’ immunity might not work on the whole population, and T-cell-mediated immunity, another arm of the immune response, seems to be more resilient to changes in the viral genome.
SARS-CoV-2’s evasion of immunity might be slowed by these constraints, but they are unlikely to stop it, said Bloom. Evidence shows that some antibody-dodging mutations do not carry large evolutionary costs, said McLellan. “The virus will always be able to mutate parts of the Spike.”
A virus in transition How SARS-CoV-2 evolves in response to immunity has implications for its transition to an endemic virus. There wouldn’t be a steady baseline level of infections, says Kucharski. “A lot of people have a flat horizontal line in their head, which is not what endemic infections do.” Instead, the virus is likely to cause outbreaks and epidemics of varying size, like influenza and most other common respiratory infections do.
To predict what these outbreaks will look like, scientists are investigating how quickly a population becomes newly susceptible to infection, says Kucharski, and whether that happens mostly through viral evolution, waning immune responses, or the birth of new children without immunity to the virus. “My feeling is that small changes that open up a certain fraction of the previously exposed population to reinfection may be the most likely evolutionary trajectory,” said Rambaut.
The best outlook for SARS-CoV-2, but also the least likely, would be for it to follow measles. Lifetime protection results from infection or vaccination and the virus circulates largely on the basis of new births. “Even a virus like measles, which has essentially no ability to evolve to evade immunity, is still around,” said Bloom.
A more likely, but still relatively hopeful, parallel for SARS-CoV-2 is a pathogen called respiratory syncytial virus (RSV). Most people get infected in their first two years of life. RSV is a leading cause of hospitalisation of infants, but most childhood cases are mild. Waning immunity and viral evolution together allow new strains of RSV to sweep across the planet each year, infecting adults in large numbers, but with mild symptoms thanks to childhood exposure. If SARS-CoV-2 follows this path – aided by vaccines that provide strong protection against severe disease – “it becomes essentially a virus of kids,” Rambaut said.
Influenza offers two other scenarios. The influenza A virus, which drives global seasonal influenza epidemics each year, is characterised by the rapid evolution and spread of new variants able to escape the immunity elicited by past strains. The result is seasonal epidemics, propelled largely by spread in adults, who can still develop severe symptoms. Flu jabs reduce disease severity and slow transmission, but influenza A’s fast evolution means the vaccines aren’t always well matched to circulating strains.
But if SARS-CoV-2 evolves to evade immunity more sluggishly, it might come to resemble influenza B. That virus’s slower rate of change, compared with influenza A, means that its transmission is driven largely by infections in children, who have less immunity than adults.
How quickly SARS-CoV-2 evolves in response to immunity will also determine the need for vaccine updates. The current offerings will probably need to be updated at some point, says Bedford. In a preprint5 published in September, his team found signs that SARS-CoV-2 was evolving much faster than seasonal coronaviruses and even outpacing influenza A, whose major circulating form is called H3N2. Bedford expects SARS-CoV-2 to eventually slow down to a steadier state of change. “Whether it’s H3N2-like, where you need to update the vaccine every year or two, or where you need to update the vaccine every five years, or if it’s something worse, I don’t quite know,” he says.
Although other respiratory viruses, including seasonal coronaviruses such as 229E, offer several potential futures for SARS-CoV-2, the virus may go in a different direction entirely, say Rambaut and others. The sky-high circulation of the Delta variant and the rise of Omicron, aided by inequitable vaccine roll-outs to lower-income countries and minimal control measures in certain large developed countries such as the US, offer fertile ground for SARS-CoV-2 to take additional surprising evolutionary leaps.
For instance, a document prepared by a UK government science advisory group in July raised the possibility that SARS-CoV-2 could become more severe or evade current vaccines by recombining with other coronaviruses. Continued circulation in animal reservoirs, such as mink or white-tailed deer, brings more potential for surprising changes, such as immune escape or heightened severity.
It may be that the future of SARS-CoV-2 is still in human hands. Vaccinating as many people as possible, while the jabs are still highly effective, could stop the virus from unlocking changes that drive a new wave. “There may be multiple directions that the virus can go in,” said Rambaut, “and the virus hasn’t committed.”
Scientists have reported identifying a ‘stealth’ version of Omicron that cannot be distinguished from other variants based on standard PCR tests.
The so-called stealth variant has a number of mutations in common with standard Omicron, but it lacks the key genetic change that makes it stand out in PCR tests. This means probable cases are not flagged by routine PCR tests, even though genomic testing can identify it as the Omicron variant.
This distinctive marker had been one of the fortunate features of the new variant, as Tulio de Oliveira, director of the Centre for Epidemic Response and Innovation in South Africa, had explained: “We can detect [Omicron] very quickly, and this will help us to track and understand the spread.”
It is still too early to know whether the new form of Omicron will spread in the same way as the standard Omicron variant, researchers say. However the ‘stealth’ version is genetically distinct and so may behave differently.
The stealth variant was first spotted among recently submitted COVID virus genomes from South Africa, Australia and Canada, but it may already have spread more widely. So far it has been detected in seven individuals.
As a result of this new variant, researchers have split the B.1.1.529 lineage into standard Omicron (BA.1) and the newer variant (BA.2).
“There are two lineages within Omicron, BA.1 and BA.2, that are quite differentiated genetically,” said Professor Francois Balloux, director of the University College London Genetics Institute. “The two lineages may behave differently.”
Whole genome analysis confirms which variant has caused a COVID infection, but PCR tests can sometimes give an indication. About half of the UK’s PCR machines search for three genes in the virus, but Omicron only tests positive for two. This is because Omicron has a deletion in the “S” or spike gene, similar to Alpha before it. This glitch means PCR tests displaying so-called “S gene target failure” strongly suggest Omicron infection.
Informally, some researchers are calling the new variant “stealth Omicron” because it lacks the deletion that allows PCR tests to spot it.
One major unknown is how the new variant emerged. While it falls under Omicron, it is so genetically distinct that it may qualify as a new “variant of concern” if it spreads rapidly. Having two variants arise in quick succession with shared mutations is “worrying” according to one researcher, and suggests public health surveillance “is missing a big piece of the puzzle”.
In a news release by Netcare, the company’s CEO Dr Richard Friedland said that more than three weeks after the discovery of the new Omicron variant in South Africa, data across its hospitals and primary healthcare facilities are demonstrating important early trends.
“Having personally seen many of our patients across our Gauteng hospitals, their symptoms are far milder than anything we experienced during the first three waves,” commented Dr Friedland.
“Approximately 90% of COVID patients currently in our hospitals require no form of oxygen therapy and are considered incidental cases. While we fully recognise that it is still early days, if this trend continues, it would appear that with a few exceptions of those requiring tertiary care, the fourth wave can be adequately treated at a primary care level.”
Rates of community transmission and hospital admission possibly decoupled During the first three waves, the rate of hospital admissions rose in tandem with the rate of community transmission (the number of people testing positive). Dr Friedland noted that, in the first three waves of the pandemic, Netcare treated 126 000 COVID patients across its 49 acute hospitals, of which 55 000 (44%) patients required admission and 26% of these patients were treated in High Care and Intensive Care (ICU). Significantly, all COVID patients admitted were sick and required some form of oxygen therapy. The high admission rate, as well as the high percentage of patients requiring ICU or High Care indicates the severity of cases during the first three waves.
“As of today we have 337 COVID positive patients admitted (72% in the Gauteng area and 18% in KwaZulu-Natal). Of these patients approximately 10% (33 patients) are on some form of oxygenation versus 100% in the first three waves. Eight of these patients (2%) are being ventilated and of these, two are primary trauma cases that are also COVID positive.”
Netcare’s policy is to test all patients for COVID before or on admission. Patients admitted for other primary diagnoses or surgical procedures who test positive for COVID] but do not require any form of oxygenation are considered to be incidental COVID cases, which currently accounts for 90% of COVID cases now in Netcare hospitals.
“During the first three waves, when the overall community positivity rate breached 26% across South Africa, we were inundated with COVID admissions to hospital. Within Netcare we had over 2000 COVID patients in hospitals during the first wave, over 2 250 patients in hospital during the second wave and over 3000 patients in hospital during the third wave. At present the 337 patients represent a fraction compared to previous waves,” said Dr Friedland.
“The very rapid rise in community transmission as compared to previous waves may partially explain this relatively low hospital admission rate. However, there does appear to be a decoupling in terms of the rate of hospital admissions at this early stage in the evolution of the fourth wave,” suggested Dr Friedland.
Majority of patients unvaccinated Dr Friedland added that of a total of 800 COVID positive patients that were admitted since 15 November, 75% of patients were unvaccinated. Netcare has seen seven deaths over this period in this group of patients, of which four may be ascribed to COVID. These four patients were 58 to 91 years of age and had significant co-morbidities. Of these patients, three were not vaccinated.
Dr Friedland observed that COVID patients admitted since 15 November are on average younger than those seen during the first three waves. Over 71% are under 50, with an average age of 38.5. This compares to only 40% below 50 in the first three waves, with an average age of 54.
Virtually all patients have presented with mild to moderate flu-like symptoms, including a blocked or runny nose, headache and a scratchy or sore throat and have been treated symptomatically.
Dr Friedland reiterated that the best way to support South Africa remains to take COVID extremely seriously and to be as cautious as ever.
While Omicron appears to be extremely transmissible and has been shown to have a greater ability to evade immunity from vaccination and prior infection, there is some evidence the Omicron variant may cause less severe disease.
In Gauteng, NICD hospital surveillance data show that 1904 COVID cases were admitted last week, and 177 COVID patients are currently in ICU with 51 ventilated as of yesterday. Nationwide, 13 147 new cases were detected with a positivity rate of 24.86%. While the fourth wave is still in the early stages, with a higher proportion of younger patients who develop less severe disease, anecdotal evidence points to reduced severity with the Omicron variant.
According to the Financial Times, preliminary data from the Steve Biko and Tshwane District Hospital Complex showed that on December 2 only nine of the 42 patients on the COVID ward, all of whom were unvaccinated, were being treated for the virus and were in need of oxygen. The remainder of the patients were COVID positive but asymptomatic and were being treated for other conditions.
“My colleagues and I have all noticed this high number of patients on room air,” said Dr Fareed Abdullah, an infectious disease doctor at the Steve Biko hospital and a director of the South African Medical Research Council.
“You walked into a COVID ward any time in the past 18 months… you could hear the oxygen whooshing out of the wall sockets, you could hear the ventilators beeping… but now the vast majority of patients are like any other ward.”
US chief medical adviser Dr Anthony Fauci remarked that initial South African data was “a bit encouraging regarding the severity”.
“Thus far, it does not look like there’s a great degree of severity to it,” he said. “But we’ve really got to be careful before we make any determinations.” Existing vaccines could provide “a considerable degree” of protection against Omicron, he added.
A small positive note for South Africa was Dr Fauci saying the administration is reevaluating the travel ban on eight southern African countries as more becomes known about Omicron and its spread.
“That ban was done at a time when we were really in the dark – we had no idea what was going on,” he said.
A new opinion piece provides an exhaustive examination of the ethics of using hospital resources on unvaccinated-by-choice COVID patients with pneumonia, versus patients with other serious but slower illnesses.
In his article published online in the Annals of the American Thoracic Society, William F. Parker, MD, PhD, looked at cases in which hospitals delayed time-sensitive and medically necessary procedures for vaccinated adults when they were overwhelmed with unvaccinated patients who had severe, life-threatening COVID pneumonia and suggested an ethical framework for triaging these patients.
“These vaccinated patients are directly harmed when hospitals use all their resources to care for the many unvaccinated patients with COVID,” he wrote. “For example, delaying breast cancer surgery by just four weeks increases the relative risk of death from the disease by 8%.”
Dr Parker argues for a contingency care standard prioritising emergency life-support, regardless of vaccination status, in order to save the most lives. “Simply rejecting the use of vaccination in prioritisation of medical resources without analysis ignores the very real tradeoffs at play during a pandemic. The pain and suffering of the vaccinated from deferred medical care require a deeper defense of caring for the unvaccinated.”
Eliminating double standards He stated: “Even though the vast majority of patients who develop life-threatening COVID pneumonia are unvaccinated, hospitals still have ethical obligations to expand capacity and focus operations on caring for them—even if it means making vaccinated patients wait for important but less urgent care like cancer and heart surgeries.”
“If tertiary care centers turn inward and stop taking transfers of COVID patients from overwhelmed community hospitals, this will result in de facto triage in favor of lower benefit care and cause systematic harm to both the vaccinated and unvaccinated in vulnerable communities,” he adds. “Hospitals must justify their nonprofit status by accepting transfers and prioritizing life-saving care during a pandemic surge.”
He cited the example of a surge in Los Angeles, when the public health department had to issue an order forcing elite hospitals to stop doing financially lucrative elective procedures and accept patient transfers from community hospitals with ICUs overwhelmed by COVID.
Reciprocity and proportionality The principle of reciprocity supports a possible tiebreaker role for vaccination status when two patients have equivalent survival benefit from a scarce health care resource. However, a universal exclusion of the unvaccinated from life support during a pandemic surge fails the test of proportionality for reciprocity, according to Dr Parker.
Reciprocity is rewarding one positive action with another. One example of this principle is giving vaccinated people access to sporting or entertainment events that are off limits to the unvaccinated (even if negative for COVID). Proportionality is the principle that ‘payback’ should be proportional to the magnitude of the act. For example, living kidney donors get moved way up the waitlist- the equivalent of four years of waiting time on dialysis. This satisfies the proportionality principle.
Dr Parker points out that while the increased relative risk of death of 8% from deferring breast cancer surgery is awful, the absolute increase in risk is only one per 100, and perhaps only one per 200 for a two-week deferral. “After the surge is over, the hospital can catch up on deferred elective surgeries,” he wrote. “The harm from a coronary artery bypass or cancer surgery delayed two weeks is real, but tiny in comparison to certain death from denying life support for respiratory failure.”
He concluded that: “There is a defensible role for vaccination status in triage as a limited tiebreaker, not as a categorical exclusion, but only in the context of a well-defined and transparent triage algorithm. Despite the enormous financial pressure to do otherwise, elite academic centres are obligated to prioritise life support for emergency conditions to save as many lives as possible during COVID surges.”
As President Cyril Ramaphosa warns that the long-expected fourth wave is upon the country, a legal battle against mandatory vaccination is brewing even as Omicron rates create an unprecedented surge, likely driven through re-infections.
Omicron, detected by South African scientists only two weeks ago, is now dominating in most provinces. However, he stressed that the country had been prepared for a fourth wave, having long been predicted by modellers. He reiterated the call for more vaccinations and to observe social distancing as much as possible over the festive season.
Vaccine mandates are now on the cards, which are expected to be introduced in early 2022. Civil rights groups including Afriforum and Sakeliga have threatened legal action if the government moves ahead on its plans to introduce vaccine mandates.
Afriforum called vaccine mandates a violation of personal freedoms, and cited Ramaphosa’s statement February this year saying that nobody in the country would be forced to take a vaccination.
As of Monday evening, reported test positivity rate now stands at 26.4%, which is well above the 10% ‘level of concern’ which had been reached a week ago.. In the third wave, it took about a month to go from this level to 25%.
At this stage, there is only anecdotal evidence around Omicron’s severity which suggests milder disease.
Prof Dame Sarah Gilbert, one of the creators of the Oxford/AstraZeneca vaccine, echoed the warning that vaccine effectiveness may be reduced against Omicron, noting its spike protein contained mutations known to increase the transmissibility of the virus. She cautioned that “there are additional changes that may mean antibodies induced by the vaccines, or by infection with other variants, may be less effective at preventing infection with Omicron.
“Until we know more, we should be cautious, and take steps to slow down the spread of this new variant.”
Preliminary results published in a preprint paper awaiting peer reviewsuggest that the re-infection hazard ratio for Omicron is 2.39, with a possible range of 1.88–3.11 falling within the 95% confidence interval. By contrast, they found that the Beta and Delta variants proliferated primarily as a result of increased transmissibility, not immune escape.
In the first head-to-head comparison of the effectiveness of the Pfizer-BioNTech and Moderna COVID vaccines, researchers examined the electronic health records of veterans who had received each vaccine and found Moderna to be slightly more effective.
The Moderna vaccine’s increased level of protection included a 21% lower risk of documented infection and 41% lower risk of hospitalisation, according to the research team, whose findings were published in the New England Journal of Medicine.
“Both vaccines are incredibly effective, with only rare breakthrough cases,” said Dr J.P. Casas, a member of the research team. “But regardless of the predominant strain – Alpha earlier and then Delta later – Moderna was shown to be slightly more effective.”
Researchers designed their comparative effectiveness study to address the previously unanswered question of which of the two mRNA vaccines is more effective. Effectiveness outcomes were: documented COVID, symptomatic disease, hospitalisation, ICU admission, and death. The investigators drew on the database of US veterans who received one of the two COVID vaccines between early January 2021 and mid-May 2021.
As initially designed, the research focused on the Alpha variant that predominated at the time. The study matched 219 842 recipients of the Pfizer vaccine to the same number of recipients of the Moderna vaccine. The two groups were matched based on a variety of clinical and demographic factors that could affect outcomes.
Over the study’s 24-week follow-up period, the estimated risk of documented infection was 4.52 events per 1000 people in the Moderna vaccine group and 5.75 per 1000 in the Pfizer group, an excess of 1.23 cases per 1000. The investigators also observed smaller excesses of symptomatic COVID (0.44 events), hospitalisation (0.55 events), ICU admission (0.10 events), and death (0.02 events) per 1000 people in the Pfizer group relative to the Moderna group.
This pattern of a lower risk for Moderna held up when Delta was the main strain. In this comparison, excess risk of documented infection over 12 weeks was 6.54 events per 1000 people for the Pfizer vaccine, compared to Moderna. Given the shorter time frame available for this supplementary research, infection was the only outcome researchers analyzed. Also, the estimates were considered less precise because a smaller number of individuals were eligible for this analysis.
Randomised trials comparing the mRNA vaccines against placebos had previously shown both vaccines to be very effective against symptomatic COVID infection (95% effectiveness for Pfizer-BioNTech, 94% for Moderna), borne out by real-world vaccine use.
“Given the high effectiveness of both the Moderna and Pfizer vaccines, confirmed by our study, either one is recommended to any individual offered a choice between the two,” said first author Dr Barbra A. Dickerman. “However, while the estimated differences in effectiveness were small on an absolute scale, they may be meaningful when considering the large population scale at which these vaccines are deployed. This information may be helpful for larger decision-making bodies.”
The massive Veteran Association records system supported a very large sample size. This, in turn, allowed the study to identify even small differences in effectiveness between the Pfizer and Moderna vaccines. The researchers used a methodology known as causal inference to mirror a gold standard randomised trial as closely as possible. Causal inference is a type of data analysis that helps researchers draw firm conclusions about cause and effect.
Using the VA database, vaccine recipients were closely matched on age, sex, race, geographic location, and other attributes that could affect COVID-related outcomes.
“After this careful matching, we found that the two vaccine groups were extremely similar in terms of variables with respect to an extensive set of demographic, geographic, and health-related attributes,” Dr Dickerman said. “This allowed our observational analysis to produce exceptionally credible results during a global emergency, when answers are needed fast and randomised trials can be impractical.”
As the global pandemic continues to unfold, the research team is working on answers relating to the comparative safety, versus effectiveness, of the Pfizer and Moderna vaccines. Dr Dickerman characterises comparative safety as an “additional piece of the puzzle to support vaccine decision-making.”
Even beyond this analysis, further evaluation of the vaccines’ comparative effectiveness and safety is needed, the authors concluded. Meanwhile, given the evidence at hand, the authors concluded about the Pfizer and Moderna vaccines considered in their study, “Given the high effectiveness and safety profile of both mRNA vaccines, either one is strongly recommended.”
The first randomised trial of COVID boosters, published in The Lancet, has shown that six are safe and provoke strong immune responses. Participants have previously received a two-dose course of ChAdOx1-nCov19 (Oxford–AstraZeneca [ChAd]) or BNT162b2 (Pfizer-BioNTech [BNT]). The announcement comes just as the Omicron variant is beginning to spread around the world.
ChAd has now been deployed in more than 180 countries and BNT in more than 145 countries. Several studies show that two doses of ChAd and BNT confer 79% and 90% protection, respectively, against hospitalisation and death after six months. However, protection against COVID infection wanes in time, which has led to the consideration of boosters. However, there are currently little data on the comparative safety of COVID vaccines, and the immune responses they stimulate, when given as a third dose.
The COV-BOOST study looked at safety, immune response (immunogenicity) and side-effects (reactogenicity) of seven vaccines when used as a third booster jab. The vaccines studied were ChAd, BNT, NVX-CoV2373 (Novavax [NVX]), Ad26.COV2.S (Janssen [Ad26]), Moderna [mRNA1273], VLA2001 (Valneva [VLA]), and CVnCov (Curevac [CVn]).
“The side effect data show all seven vaccines are safe to use as third doses, with acceptable levels of inflammatory side effects like injection site pain, muscle soreness, fatigue. Whilst all boosted spike protein immunogenicity after two doses of AstraZeneca, only AstraZeneca, Pfizer-BioNTech, Moderna, Novavax, Janssen and Curevac did so after two doses of Pfizer-BioNTech”, commented Professor Saul Faust, trial lead.
“It’s really encouraging that a wide range of vaccines, using different technologies, show benefits as a third dose to either AstraZeneca or Pfizer-BioNTech. That gives confidence and flexibility in developing booster programmes here in the UK and globally, with other factors like supply chain and logistics also in play”, added Prof Faust.
“It’s important to note that these results relate only to these vaccines as boosters to the two primary vaccinations, and to the immune response they drive at 28 days. Further work will generate data at three months and one year after people have received their boosters, which will provide insights into their impact on long-term protection and immunological memory. We are also studying two of the vaccines in people who had a later third dose after 7-8 months although results will not be available until the new year.”
A randomised, phase 2 trial of seven booster vaccines was conducted, with the third doses given 10-12 weeks after initial two-dose courses of ChAd or BNT. The trial involved 2878 healthy participants between June 1st and June 30th 2021. Participants had received their first doses of ChAd or BNT in December 2020, January or February 2021, and second doses at least 70 days before enrolment for ChAd and at least 84 days for BNT. About half of participants received two doses of ChAd and half two doses of BNT. The control vaccine used was a meningococcal conjugate vaccine (MenACWY).
Participants were aged 30 or older, roughly half of whom were 70 or older. The average age of participants who received ChAd was 53 years in the younger age group and 76 years in the older age group. Average ages for BNT were 51 and 78 years, respectively.
Thirteen experimental and control arms of the trial (seven vaccines plus three at half dose and three control arms) were split into three participant groups. Group A received NVX, half dose NVX, ChAd, or a control. Group B received BNT, VLA, half dose VLA, Ad26 or a control. Group C received Moderna, CVn (development of which was halted in October 2021), half dose BNT, or a control.
Primary outcomes were adverse effects seven days after receiving a booster, and levels of antibodies targeting the SARS-CoV-2 Spike protein after 28 days, compared to controls. Secondary outcomes included the response of T cells to wild type, Alpha, Beta, and Delta variants.
Increases in anti-spike protein antibody levels after 28 days varied across the vaccines. After two doses of ChAd these ranged from 1.8 times higher to 32.3 times higher according to the booster vaccine used. Following two doses of BNT, the range was 1.3 times higher to 11.5 times higher. Significant T-cell responses were reported in several combinations.
At 28 days, all booster results were similar for participants aged 30-69 years and those aged 70 years or older. Boost ratios should be interpreted with caution, the authors caution, since they relate to immunogenicity rather than protection against disease, and the relationship between antibody levels at day 28 and long-term protection and immunological memory is unknown.
Reactions to all seven vaccines were similar, with fatigue, headache, and injection site pain most often reported. These were more commonly reported by those aged 30-69. 912 of the 2878 participants experienced a total of 1036 adverse events, 24 of which were severe.
