As the COVID-19 pandemic accelerates around the world, many low- and middle-income countries (LMICs) are still struggling to access the diagnostic tests they desperately need to bring the disease under control.
On June 24, the World Health Organization (WHO) reported that there have now been more than 9 million confirmed cases of COVID-19 globally, causing almost half a million deaths. Contained in these dreadful numbers are some notable spikes in LMICs. India, for example, logged its highest daily rise in new infections, adding almost 16,000 to reach a running total of 456,000, while its COVID-19 death toll increased to more than 14,000. And Latin American countries have now confirmed more than 2 million cases, with Brazil, Peru, Chile, and Mexico the worst affected.
As WHO Director-General Tedros Adhanom Ghebreyesus said last week, “the world is in a new and dangerous phase.”
LMICs are particularly vulnerable to the surging pandemic. Many have no domestic capacity for manufacturing diagnostic tests, and rely heavily on imports. But with global supplies at a premium, LMICs either cannot afford pricey analytical equipment or reagents, or are simply unable to find manufacturers willing to supply them. Many of these manufacturers have targeted their products at larger markets in Europe and North America—partly because that is where the most cases have occurred in recent months, but also because economically powerful countries can outbid LMICs for limited supplies.
“We get desperate calls from laboratories, from governments [in LMICs], every day, about supply challenges,” says Catharina Boehme, chief executive officer of the Foundation for Innovative New Diagnostics (FIND), a global nonprofit organization based in Geneva.
FIND and other groups aim to boost testing capacity in LMICs. Some of these organizations’ initiatives are helping groups of LMICs to coordinate their procurement efforts to ensure more equitable access to diagnostics at affordable prices. Others are providing independent validation of tests, giving LMICs confidence that the kits they buy will be effective. And efforts are afoot to give the countries independence by building up local manufacturing capacity for COVID-19 and other diagnostics.
Finding testing solutions
Since it was founded in 2003, FIND has been involved in developing 24 new diagnostic tools for infectious diseases such as tuberculosis, malaria, and sleeping sickness. FIND works with manufacturers to develop reliable, low-cost assays for diseases that affect the world’s poorest people and also provides independent assessments to ensure that tests meet WHO quality standards.
In early February, the WHO asked FIND to turn its attention to COVID-19 and support policy makers and health-care providers with information about COVID-19 diagnostics. For example, FIND keeps a database of all COVID-19 diagnostic assays that are currently available or in development. By June 25, it had logged 734 tests. The emergency use authorizations so far issued by regulators such as the US Food and Drug Administration have enabled manufacturers to put these products on the market with very limited clinical or analytical evaluation. But before LMICs invest in these technologies, governments usually want to see independent evidence about their performance.
So FIND is carrying out independent evaluations of some of these tests to assist procurement decisions in LMICs. The organization not only measures the sensitivity and specificity of the tests—which predict the number of genuine positive and negative results, respectively, that a test can deliver—but also grades them on criteria such as their availability in LMICs, or whether they require scarce analytical equipment. “FIND’s work on independent evaluation of test kits has been helpful,” says Yenew Kebede Tebeje, head of laboratory systems at Africa Centres for Disease Control and Prevention (Africa CDC). FIND also provides online training on how to carry out diagnostic tests and advice about the most appropriate tests for particular uses in different countries.
COVID-19 diagnostic tests broadly fall into three categories. Nucleic acid tests, also called molecular tests, are the gold standard to diagnose current infections. They detect RNA from SARS-CoV-2, the virus that causes COVID-19, in samples swabbed from a patient’s nose or throat, and typically rely on reverse transcriptase polymerase chain reaction (RT-PCR). This process converts RNA into DNA and then amplifies many copies of the genetic material. Antigen tests can detect viral proteins in swabs or blood samples, although relatively few of these diagnostics have been validated for COVID-19. Meanwhile, antibody tests can probe blood samples for antibodies that patients have developed against the virus, indicating a past infection and giving some hope that the people may have temporary immunity against the virus. These antibody tests include enzyme-linked immunosorbent assays (ELISA) that are performed by trained staff in a lab, as well as rapid diagnostic tests (RDTs) that show their results as a colored band on a small test strip, like a lateral-flow home pregnancy test.
Each test has its strengths and weaknesses. Although nucleic acid tests offer the highest selectivity and sensitivity, they also tend to be slower and more expensive. RDTs offer lower sensitivity and specificity and can vary widely in their accuracy, but they are fast, cheap, and easy to use.
FIND’s analysis of the available COVID-19 tests helped Peru shape its response to the pandemic, says Patricia J. García at Cayetano Heredia University (UPCH), who was previously the country’s minister of health and is a former head of the Peruvian National Institute of Health. She recalls the government’s fruitless quest for diagnostic resources when the first cases appeared in March. “We started trying to buy reagents for molecular testing, and although we had the money, it was impossible to find them,” she says. At the time, Peru had only a handful of labs able to conduct the preferred RT-PCR tests for COVID-19, so the country’s relatively small reagent order made it a minor player in the global procurement scramble.
So Peru quickly pivoted. With the help of information from FIND, the country acquired 1.4 million rapid antibody tests from Chinese suppliers. Some antibodies can appear 5 to 7 days after a patient develops symptoms, while they are still infectious, so Peru is using these tests to help triage symptomatic patients and also to track overall infection rates. “Most of our cases are reported on the basis of these serological tests,” she says, adding that case numbers are thankfully now plateauing in Lima.
Companies across the globe have submitted their tests to FIND for evaluation, hoping that a stamp of approval will spur wider use, but the organization has focused its efforts on products that can be produced at large scale and sold to LMICs at an accessible price. More than 60 tests meeting these criteria are either currently in evaluation or have already been evaluated. The organization also provides LMICs with data from independent evaluations carried out by national regulators and academic groups. “We hear from a lot of countries who do not have the capacity to validate their own test kits, and they are definitely finding these evaluations very useful,” says Sanjay Sarin, head of FIND India.
Indian regulators have approved some RT-PCR test kits made by Indian manufacturers, but Sarin says that the country is still largely dependent on imports, and the extraction kits needed to prepare samples for RNA testing are in short supply. And although India has approved roughly 700 labs to conduct COVID-19 testing, those labs often rely on manual RNA extraction, which has slowed down processing of samples. “What is needed now is a point-of-care diagnostic machine, which can be very easily deployed in a health-care center,” Sarin says.
Many point-of-care RT-PCR devices are plug-and-play instruments, which contain fluorescence detectors, pumps, and other machinery. Samples are plugged into the device on a disposable microfluidic chip or cartridge that contains a disease-specific assay.
Abbott’s portable ID NOW device, for example, can be used for SARS-CoV-2 RNA detection, and delivers results in under 15 minutes. But sales are largely restricted to the US market.
So Molbio Diagnostics, based in Goa, India, is now offering an alternative. It has developed a SARS-CoV-2 test on a micro-PCR chip called Truenat, which the Indian Council of Medical Research approved in May. The chip plugs into Molbio’s Truelab portable RT-PCR devices, which also come with an automated sample preparation system. There are already about 1,200 of these battery-powered PCR machines across India because they are commonly used for tuberculosis and HIV diagnostics, which use different Truenat chips. FIND supported the development of the Truenat tuberculosis assay and evaluated its performance, which helped to spur wider adoption of the technology in the country.
In Africa, most COVID-19 cases have occurred in major cities, but the disease is spreading rapidly to other areas. As of June 25, the Africa CDC had logged more than 330,000 confirmed cases across Africa and almost 9,000 deaths. Those numbers are likely to be underestimates: most African countries have carried out fewer than 500 tests per 100,000 people in their populations, a far lower rate than higher-income countries. The United States, for example, has done more than 8,300 tests per 100,000 people, according to FIND.
Cheaper tests could help to turn this around. For example, UK-based diagnostics manufacturer Mologic has developed a low-cost RDT that can detect three COVID-19 antibodies (IgA, IgM, and IgG) within 10 minutes, with a sensitivity of up to 96% and a specificity of 98.8%.
To carry out the test, a clinician spots a patient’s blood sample onto a nitrocellulose strip inside the device. Three separate bands of antibodies are bound to the strip that can capture IgA, IgM, and IgG as the sample moves across the nitrocellulose.
Adding a mixture of three SARS-CoV-2 proteins, each connected to a gold nanoparticle, can then reveal these captured antibodies. As the proteins bind to IgA, IgM, and IgG, gold nanoparticles accumulate on each band and produce a deep red color. These tests could help with clinical triage, and for population-wide surveillance of the disease, says Joe Fitchett, medical director of Mologic.
FIND will soon carry out head-to-head trials of Mologic’s antibody test against other RDTs. “I expect it will be one of the most specific tests out there, and I think we’re going to be the cheapest,” Fitchett says.
With financial support from FIND and the Bill & Melinda Gates Foundation, the company has built an automated manufacturing facility for the tests next to its labs in Thurleigh, UK. Once it starts production on July 1, the facility should be able to make about 40 million tests per year. Thanks to the automation, the simplicity of the test, and bulk procurement of the reagents, Mologic thinks the tests will cost a little over $1 apiece and will be sold to LMICs at cost, so the company won’t make a profit from their sale.
The RDTs will also be made at DiaTropix, a new facility in Senegal, at a cost of $1 per test. The center sprung from a prior collaboration involving Mologic, the Pasteur Institute of Dakar, FIND, and other partners. Intended to produce tests for diseases such as Ebola, dengue fever, measles, and yellow fever, the facility was completed in April. But it has now been repurposed to make COVID-19 tests, and should begin production in July, with an initial capacity of 4 million units per year.
Not only will DiaTropix shorten supply chains in Africa, it will also help to build longer-term capacity in diagnostics production. “There is an imperative for this capability to be more equitably distributed across the world,” Fitchett says.
The COVID-19 pandemic has emphasized long-standing weaknesses in health-care manufacturing capacity in Africa, says Christoph Spennemann, an intellectual property lawyer at the United Nations Conference on Trade and Development. But international collaborations like the one behind DiaTropix can offer a valuable way to build much-needed capacity and reduce reliance on health-care imports. “These are the kinds of partnerships we’re trying to promote,” Spennemann says.
More cooperation between African countries should also help. For example, the African Union and the Africa CDC have launched the Partnership to Accelerate COVID-19 Testing (PACT), which includes a coordinated procurement system. “We expect this to be extremely useful, as it links companies with member states and logistics providers,” says the Africa CDC’s Tebeje. Along with additional support for scale-up of local manufacturing, PACT aims to ensure that at least 10 million Africans are tested by the end of October.
That effort will be vital—not only for Africa, but for the whole world. “We cannot stop this pandemic unless every laboratory can access the reagents it needs,” Fitchett says.