Can Serology Tests and Seroprevalence Surveys Inform a More Effective Vaccine Roll Out?

Vaccines have become a central instrument of our long-term response to the pandemic. Vaccination campaigns have now started around the world and will confer significant direct protection against infection, severe illness, and death to those inoculated. It may also protect against transmission, though robust evidence is yet to be confirmed.

COVAX, the global initiative established to facilitate vaccine supply access in eligible countries, has delivered an estimated 80 million vaccines to 129 low- and middle-income countries (LMICs) since Ghana received the first shipment back in late February. COVAX has set initial targets to provide sufficient vaccines to vaccinate 20 percent of participating countries’ populations by the end of the year. In parallel to COVAX, many LMICs have received bilateral vaccine donations and are negotiating directly with manufacturers to secure additional doses to expand coverage. However, equitable access to vaccines has become one of the most pressing issue of the year, especially in LMICs where widespread vaccination could take years.

How can we roll-out scarce vaccines to maximise benefits to population health? Last November, the WHO published a roadmap for prioritising uses of COVID-19 vaccines in the context of limited supply, outlining potential benefits from prioritising different population groups. However, this roadmap does not include information on whether and how serology tests and seroprevalence surveys could support an impactful roll-out, as this remains an important source of uncertainty. This is an important question in countries that have experienced significant, recent previous waves of infections, and as a result, which may have higher natural immunity in the past year. Here, we discuss new evidence on this topic, articulate current sources of uncertainty and evidence gaps, and identify strategies that may be considered in LMICs.

What do serology tests and seroprevalence surveys tell us?

Serology tests, which detect the presence of antibodies produced against a pathogen within an individual’s blood, can indicate whether an individual has previously been infected by SARS-CoV-2, the virus that causes COVID-19. Antibodies confer immunity in most people for a certain duration of time (although the strength of the overall immune response will differ on a case-by-case basis, including potential longer-term protection from other parts of the immune system). This means that a proportion of individuals with a recent COVID-19 infection will not experience a new infection for a certain amount of time (this does not eliminate potential reinfection by the same virus type, or more likely, by new variants that may escape immunity from infection).

Serological surveys can be used to retrospectively measure disease prevalence in specific communities or populations such as schools, hospital workers, military officials, and nursing homes. They are also used to map how the epidemic changes over time or give indications on how it is transmitted. Surveys are important because relying on reported COVID-19 cases risks significantly under-estimating the true number of infections, given (i) weak testing capacity in many LMICs, (ii) the significant proportion of individuals who are asymptomatic or only mildly symptomatic and therefore less likely to be tested, and (iii) challenges in data and surveillance systems. Serological data may be used to provide guidance to governing bodies for instituting mitigation strategies for COVID-19, including developing effective non pharmaceutical interventions and vaccine prioritisation. In the UK, it is one of the key pillars of the COVID-19 response and informs the use of public health measures. For interested readers, SeroTracker is a systematic review of SARS-CoV-2 serosurveys globally.

Serology tests and seroprevalence survey come with their own challenges. Almost 700 serology tests have been developed to detect SARS-CoV-2 antibodies, with varying degrees of accuracy. This disparity is the result of different techniques and inadequate regulatory oversight to guarantee performance and quality before tests enters the market, a problem compounded in most LMICs where regulatory capacity is lacking. In Africa, experts have expressed concerns about the validity of those surveys and about the cross-reactivity of serology tests with other circulating viruses. Moreover, in order to be linked to decision-making, such surveys would need to be conducted on a regular basis and their results be available in a timely manner. However, serological surveys are “costly, consume staff time, require large populations, and are methodologically challenging to provide unbiased representative data”, which may prove challenging in low resource, already constrained settings.

Should we consider different vaccination or prioritisation strategies for those known to have been previously infected?

The answer is not straightforward. There are still important uncertainties around: (i) differences in protection between natural and vaccine acquired immunity, (ii) length of protection, and (iii) impact of vaccination on individuals with a previous infection.

Most experts agree that vaccine acquired immunity and naturally acquired immunity are different. The body of infectious disease knowledge tells us there are some pathogens where vaccine acquired immunity is stronger and vice-versa – it depends on both the pathogen and the type of vaccine. We don’t have the answer in the case of COVID-19. Several studies have now shown that recovery from COVID-19 likely triggers immunity lasting at least six months (in at least 95% for eight months in one study or 84% for seven months in another major study). However, there is likely to be heterogeneity in the duration of protection, which may be affected by disease severity of the first infection or age. As a benchmark, both Moderna and Pfizer/BioNtech have demonstrated 95% effectiveness against symptomatic COVID-19; although the duration of protection is still unclear. In general, there is still uncertainty about the longevity of immunity, for both natural or vaccine acquired immunity. Finally, a last complication is the already significant and still growing impact of variants, which may escape immunity to some degree. However, this concern applies for both vaccine-mediated and natural immunity (as seen in Manaus, Brazil and other major variants of concern).

Given this uncertainty, the WHO (through the SAGE interim recommendations on vaccines) advises that people who have been previously infected are still vaccinated, though this may be delayed if the infection was recent. Many countries have since followed this guidance in prioritisation strategies. However, emerging evidence from multiple contexts (see the following three studies: 1, 2, 3)  suggests that the antibody response after a single dose of an mRNA vaccine (Pfizer or Moderna) in those with a confirmed previous SARS-CoV-2 infection could be equal to or exceed the antibody response from two doses in SARS-CoV-2-naïve patients. This supports a potential strategy for using a single dose or possibly deprioritising patients with a recent laboratory confirmed COVID-19 positive test. Moreover, additional evidence shows that a single dose in previously infected individuals may induce an increased response against current variants of concern, compared to a reduction after a single dose in naïve patients. This may further enhance the impact of such an approach, given the concerns on variants.

What are the implications for vaccine roll-out?

Despite the numerous sources of uncertainty discussed above (e.g. about serology tests, seroprevalence surveys, natural and vaccine induced immunity), the incorporation of information on individual serology or seroprevalence may help in maximising the impact of vaccines on the ground. We discuss three strategies that are currently on the table, although each still need to be addressed by further research:

• Prioritising individuals that have not experienced a recent COVID-19 infection. This strategy has been used in some countries to manage short-term supply issues, although mostly in high-income countries. For instance, in France, the recommendation is to wait three months from the date of confirmed COVID-19 infection to schedule a vaccination appointment. This could be envisaged in countries with a current active outbreak and shortages of vaccines may consider a similar strategy. An exploratory modelling study in the US conducted last year showed that there were clear health benefits to allocating vaccines to those with no prior infection as a priority, even when accounting for uncertainties in seroprevalence estimates and seroreversion. However, this would require linking vaccination and testing data effectively, which may be difficult and not cost-effective settings, where health information systems and infrastructure are typically weak. This strategy would also be most effective if implemented in settings where infections are confirmed through widespread high-quality testing. Again, this will have important cost implications.
• Allocating one booster dose (of mRNA vaccines) to those with a recent confirmed positive COVID-19 test. This could help achieve more value with the vaccines available. The allocation of one booster dose could also have implications on vaccine product selection (i.e., the use of Pfizer and Moderna in LMICs may be more feasible and cost-effective if only one dose is required). It is worth noting that the current evidence only applies to mRNA vaccines and there is currently a knowledge gap for vaccines using different mechanisms (e.g. live inactivated viruses). The vast majority of vaccines administered in LMICs are not mRNA vaccines (e.g. AstraZeneca, Sinopharm).
• Prioritising allocation of vaccines in populations where natural immunity is low and where there is growing community transmission (e.g., rural vs urban, provincial/regional allocations). At least two studies are investigating this issue in the United States and India (forthcoming, although presented here). This would require a more active and dynamic approach to conducting seroprevalence surveys to reflect changing epidemics in LMICs and would only be effective if detection of rising transmission was early and medium term supply of vaccines (e.g. six months) could be guaranteed. Strategies to target resources to high-risk populations has been done previously with other diseases such as malaria.

If backed by research (including further clinical trials on the booster dose), some of those solutions would also require significant investments to improve serology test technologies and seroprevalence surveys, as well as support effective adaptations in roll out (e.g., linking testing and vaccination systems and data, supply logistics) in LMICs. Those investments will come at a significant cost and may also impact the speed of vaccination (given logistics), which will vary widely depending on the strength of the country’s health and surveillance systems. Those may not always be feasible given significant opportunity costs or may not be a priority given slow vaccine roll-out and uptake (as recently observed in DRC).

However, given the current challenges globally, all options should be considered for improving the impact of vaccine campaigns.