Dhaka Courier

Closer to Immunity

After a week of high geopolitical drama in which nearly every scab on the wounded body of bilateral relations between Britain and China was brutally exposed, this past week started with a glimpse into possibilities. But in the slipstream of last week’s decisive and momentous shifts, no one was in the mood to consider an ameliorative. Just to refresh your memories, the preceding week had started with China and Iran moving into an-all-but-inevitable embrace in the Middle East, before Britain dropped Huawei from their 5G network, irritated Beijing over Hong Kong and ended with the BBC calling in the Chinese Ambassador in London to their studios for an interview that to the Chinese will have counted as an ambush

So when The Lancet, the most esteemed journal in the medical science community, published two studies on the same day reporting the very encouraging findings of two separate Coronavirus candidate vaccine trials - one from Britain, the other from China - there could be no mutual backslapping or sharing of notes, understandably. Yet the way that developed into shutting each other out completely, or at least trying to through the media arms each has built up over the years, was indicative that even their best representations on behalf of humanity will not be spared the vanity and pettiness of great power rivalry- the one between the US and China, that is slowly but surely pervading each corner of the modern world, from maps to hospital beds.

Scientific research of the kind that goes into developing vaccines will see things probably heat up further. But to start off, we owe it to the scientists who have been working at a record clip to free us from the clutches of a lethal pandemic, to report their findings first.

The two candidates in question happen to be one has come to be known as the ‘Oxford vaccine’ owing to its base at the Jenner Institute at Oxford University, with support from AstraZeneca, and the second from investigators supported by CanSino Biologics in Wuhan, China.

Both groups used an adenoviral vector (human adenovirus 5), and both report the vaccine achieving humoral responses to the SARS-CoV-2 spike glycoprotein receptor binding domain by day 28 as well as T-cell responses. Both report local and systemic mild adverse events such as fever, fatigue, and injection site pain. Most encouragingly, in neither trial was a severe adverse event reported.

Dig deep

Andrew Pollard and colleagues report their phase 1/2 randomised trial of one injection of chimpanzee adenovirus-vectored COVID-19 vaccine. Vaccine formulation at one concentration was tested against a comparator quadrivalent conjugate meningococcal vaccine among 1077 healthy adults (50% male, 90•9% white) aged 18–55 years (median 35 years, IQR 28–44), recruited from five centres in the UK and followed up for 28 days. Local and systemic adverse events such as fatigue, headache, and local tenderness occurred commonly in COVID-19 vaccinees, but were tolerable and mostly ameliorated by paracetamol. No serious adverse events occurred. Neutralising antibodies were generated in more than 90% of participants across different assays. Responses were sustained up to 56 days of observation. A small non-randomly selected, second-dose boosted subset showed strong neutralising responses, and few mild adverse events. Importantly, T-cell responses were induced in all participants.

From Wuhan, Wei Chen and colleagues report results from a phase 2 randomised trial of one injection of non-replicating adenovirus-vectored COVID-19 vaccine. Vaccine formulation at two concentrations (ie, 1 × 1011 or 5 × 1010 viral particles per mL) were tested against placebo among 508 healthy COVID-19 unexposed adults (50% male) aged 18-83 years (mean 39•7 years) recruited from one centre in Wuhan, China, and followed up for 28 days. Adverse events such as fever, fatigue, headache, or local site pain occurred by day 28 in 294 (77%) of 382 vaccinees and 61 (48%) of 126 placebo recipients. Male sex was associated with lower occurrence of fever post-vaccination. No serious adverse events occurred.

Seroconversion occurred in more than 96% of participants, and neutralising antibodies were generated in about 85%. More than 90% had T-cell responses. People older than 55 years of age had somewhat lower humoral responses (although still higher than placebo), as did people with previous vector immunity, but these factors did not affect T-cell responses. Immunogenicity did not differ by sex.

These trial reports were hugely anticipated. The results of both studies augur well for phase 3 trials, where the vaccines must be tested on much larger populations of participants to assess their efficacy and safety. Overall, the results of both trials are broadly similar and promising, notwithstanding differences in the vector, in the geographical locations of the populations studied, and the neutralisation assays used.

Without drawing causal inference, the exploration of associations of age and sex with adverse events and immunogenicity reported by Chen and colleagues, and of longevity of response by Pollard and colleagues, are welcomed, given the differential burden of severe outcomes in older adults, and the emerging science around differential sex-specific vaccine effects. These COVID-19 vaccine trials are small so inferential caution is warranted, but the explorations are laudable. Ethnic diversity in both these trials was very limited.

Sticking to science

Both trials used adenovirus vectors to deliver and study the COVID-19 vaccine, an innovative and efficient means of vaccine development in the midst of a pandemic. Capable of generating humoral (in the bodily fluids), cellular, and innate responses, adenovirus-vectored vaccines have much potential. But we must bear in mind that the platform only achieved European Commission regulatory licensure on July 1, 2020, with the Ebola vaccine. Much remains unknown about these and other COVID-19 vaccines in development, including longevity of response and immunogenicity in older adults or other specific groups, such as those with comorbidities who are often excluded from clinical trials, or ethnic or racial groups more severely affected by COVID-19.

What should phase 3 trials look like? They should be rapid, pragmatic, and large enough to address efficacy in subgroups of interest, according to The Lancet. Will a single dose be sufficient in older adults, or is a booster dose required? Does longevity of response or rates of waning differ with a two-dose regimen, and does longevity of clinical protection require cell-mediated responses? Are there host-specific differences in immunogenicity by age, sex, or ethnicity? Do T-cell responses correlate with protection irrespective of humoral titres? Are there specific adverse events in pregnant women? As hotspots for infection shift, trial designs that are responsive to differential risk, or that are enriched for networks of infection, should be deployed.

The safety signals from these two important trials are reassuring. But when things are urgent, we must proceed cautiously. The success of COVID-19 vaccines hinges on community trust in vaccine sciences, which requires comprehensive and transparent evaluation of risk and honest communication of potential harms. Hand in hand with the trajectory of vaccine study, pharmacovigilance infrastructure is urgently needed, including surveillance for asymptomatic infection among vaccinated and unvaccinated persons if both absolute and relative risk of adverse vaccine outcomes, such as enhanced disease, are to be determined. These should be implemented in parallel with phase 3 trials and in preparation for phase 4 roll-out. Such infrastructure will be needed across a wide range of populations and settings, and for the spectrum of upcoming COVID-19 vaccines.

Equitable distribution of future COVID-19 vaccines also requires detailed evaluation of local country needs and priorities, community engagement, and trust. Global planning is underway, but should be underpinned and informed by specific local realities. Only this way can these very encouraging first early-phase randomised trial results yield the global remedy for which we all yearn.

The politics

Even though The Lancet published the reports on the same day, and there was very little to choose between the two sets of results reported, the highly charged geopolitical climate there was a distinct and very deliberate myopia among the two principal groups of stakeholders. The media in the UK largely ignored the results from Wuhan, and China’s constellation of English-language outlets largely did the same for the Oxford one.

It was ironic that officials from the two countries were still going at it over Huawei and Hong Kong. Some headlines from the Global Times landing page on Monday gives some idea: Beijing may target British companies if 10 Downing Street sanctions China, Little effect on China as UK ends extradition treaty with HKSAR to please US, Chinese investment will be cautious as UK leans to US, and Huawei not a 'China First' case to be confused with America First.

After intensive research, Prof Sarah Gilbert, from Oxford’s Jenner Institute, said they were more than happy with the first results, which showed good immunity after a single dose of vaccine.

“We’re really pleased that it seems to be behaving just as we thought it would do. We have quite a lot of experience of using this technology to make other vaccines, so we knew what we expected to see, and that’s what we have seen,” she told the Guardian.

The British prime minister, Boris Johnson, called the results “very positive news”, adding: “There are no guarantees, we’re not there yet and further trials will be necessary – but this is an important step in the right direction.”

His health secretary, Matt Hancock, said: “Very encouraging news. We have already ordered 100 million doses of this vaccine, should it succeed.”

Gilbert and her colleagues, who once said they could have a vaccine by September, will not predict when it might be available. “None of us have a crystal ball,” she said.

But do the antibodies last?

How well do antibodies to Sars-CoV-2, the virus which causes Covid-19, protect against reinfection by the virus? It is a question which hovers over so much research into the disease – and which ultimately will determine the success of a possible vaccine. But as yet, evidence on this crucial matter is limited. There have been several cases, in China and South Korea, of people testing positive for the virus after apparently recovering, but has subsequently become clear that the test was picking up fragments of the virus from the initial infection – not from a new infection.

This week, Science magazine publishes the results of a study which give us a little more insight. A team from Peking Medical College in Beijing exposed six macaques to Sars-Cov-2. All developed symptoms in their respiratory and gastrointestinal tracts. Twenty eight days later, when they were recovering from the disease, four of them were exposed to the virus a second time.  Each developed a transient fever which they had not shown following the initial infection. However, they had no other signs of disease, and they tested negative for active presence of the virus.

Interestingly, however, the macaques who were exposed to the virus a second time ended up with higher levels of antibodies than those animals which were exposed only once. It suggests that someone who has been infected with Covid-19 could boost their immune response to the virus by secondary exposure without developing the disease a second time.

The work builds on a study led by Harvard Medical School in May, also involving macaques, which similarly found that infection with Sars-CoV-2 provided immunity from further infection.

There are obvious caveats: neither study involved humans and both involved very small numbers of animals. But, combined with lack of evidence of any humans who have suffered from Covid-19 a second time, we are beginning to build a picture that, yes, it does seem that infection with Sars-Cov-2 provides immunity from reinfection, at least for a limited time. What we don’t know yet is whether the levels of antibodies produced by the vaccines currently under development will be sufficient to protect against infection when a vaccinated individual comes into contact with the actual virus.

Phase One and Two tests of the Oxford and Wuhan vaccines have only shown that vaccination produces antibodies, not whether they are effective against the virus. That is the purpose of the Phase Three trials which are now beginning – where several thousand vaccinated individuals will be tracked to see how many, if any, of them go on to contract the disease in the community.

And who is going to get it?

Then comes the million, nay 15.5 million (the number of confirmed cases globally as of July 24, according to Johns Hopkins University tracker) dollar question: once we’ve got a vaccine that works, or is decided upon as best-suited to the purpose of ending the pandemic, how will it be distributed and administered? Who would get it first?

Well, to answer the second question first, where the winning candidate is developed can be expected to play a big part in this. Activists warn that without stronger attempts to hold political, pharmaceutical and health leaders accountable, vaccines will be hoarded by rich countries in an unseemly race to inoculate their populations first. After the recent uproar over the United States purchasing a large amount (just some 95 percent) of the world’s supply of Remdesivir, a new experimental drug that proved useful as a therapeutic to treat COVID-19, some predict an even more disturbing scenario if a successful vaccine is developed.

To be fair to the US, it is not just some big country with the financial clout to bend pharmaceutical companies to their will, or just generally do their bidding. As  the worst-affected country on earth, you can understand its desperation. The combination of the epidemic and election year in America, without even getting into the polarising figure of President Trump defending the White House, has yielded the most macabre and mindless outbreak playing out in front of the eyes of the entire world for much of 2020. Just a tick under 145,000 Americans are already dead, with 200,000 slated to die by Election Day. Things are going to get messy there, and the rest of the world may just have to let it sort out its issues. In the days ahead, expect more announcements like the one that the Trump administration will pay Pfizer nearly $2 billion for a December delivery of 100 million doses of a COVID-19 vaccine the pharmaceutical company is developing, with the option to buy another 500 million doses, if the vaccine is safe and effective.

Where would that leave countries like Bangladesh? The key initiative to help them is led by Gavi, a public-private partnership started by the Bill & Melinda Gates Foundation that buys vaccines for about 60% of the world’s children. Last month, Gavi and the Coalition for Epidemic Preparedness Innovations (CEPI) signed a $750 million deal with AstraZeneca to give developing countries 300 million doses of the shot being developed by Oxford University. But that deal happened after the drug company had already signed contracts with Britain and the U.S., who are first in line to get vaccine deliveries in the fall.

The World Health Organization has previously said it hopes to secure 2 billion doses for people in lower-income countries by the end of 2021, including through initiatives like Gavi’s.

Chinese President Xi Jinping has also vowed to share any COVID-19 vaccine it develops with African countries — but only once immunization has been completed in China. Similar promises have been made to Bangladesh as well. China has said Bangladesh will get priority in terms of cooperation and support if they can successfully develop vaccine for the coronavirus.

"Of course, Bangladesh is our important friend and Bangladesh will surely get priority," Deputy Chief of Mission at the Chinese Embassy in Dhaka Hualong Yan told our sister newsagency UNB last month.

And so when the Bangladesh Medical Research Council this week approved the phase-3 trial of a vaccine, developed by Chinese firm Sinovac (not the CanSino one), we thought things were looking up in that direction. Mysteriously though, this has since been walked back by the government, at least somewhat.

A new health secretary struck a line that the trial of a COVID-19 vaccine is an issue that the two governments would have to agree to, which of course no one will deny. But who would’ve thought the BMRC approval came without the government being taken into confidence? The health secretary also said that the foreign ministry and top government policymakers were reviewing the prospects of the trial being conducted here. Yet somewhere you could sense, the pieces had moves on some geopolitical chessboard to scupper it.

  • Approaching Immunity
  • Oxford vaccine
  • Britain and China
  • Geopolitical Drama
  • Vaccine
  • SARS-CoV-2
  • Covid-19

Leave a Comment