By Micaela A. Witte and Philip R. Fischer, MD, DTM&H

Ms. Witte is a student at Mayo Clinic Alix School of Medicine. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Ms. Witte and Dr. Fischer report no financial relationships relevant to this field of study.

SYNOPSIS: Transplacental antibodies against Plasmodium falciparum Schizont Egress Antigen-1 may protect infants from severe malarial infection during the first year of life. This new knowledge about these antibodies potentially can inform vaccine development.

SOURCE: Kurtis JD, Raj DK, Michelow IC, et al. Maternally derived antibodies to Schizont Egress Antigen-1 and protection of infants from severe malaria. Clin Infect Dis 2019;68:1718-1724.

Falciparum malaria kills approximately 300,000 African children each year. Children older than 6 months of age are at the greatest risk. In contrast, neonates and young infants seem to be relatively spared from severe malaria infection. Although it has been hypothesized that this protection is a result of the transplacental transfer of maternal antibodies, the specific maternal antibody had not yet been identified.

Thus, Kurtis and colleagues studied 647 newborns in Tanzania for one year after birth to determine whether levels of anti-Schizont Egress Antigen-1 (PfSEA-1) in cord blood were predictive of protection against severe malarial infection. On the day of birth, maternal peripheral, placental, and cord blood were collected from 647 infants in a northeast Tanzania hospital. These infants were monitored every two weeks for one year with wellness checks that included blood smear analysis. Ultimately, complete follow-up data were collected from 583 infants.

Overall, 166 infants developed a severe malarial infection within the first 12 months of life, as defined by a positive blood smear and at least one symptom of severe infection (i.e., respiratory distress, severe anemia, temperature greater than 40° C, convulsions, hypoglycemia, or prostration). Cord blood levels of anti-PfSEA-1 were negatively correlated with severe infection. When grouped by level of anti-PfSEA-1, infants with levels in the top 10% had 51.4% fewer cases of severe malarial infection compared to infants with lower levels. Importantly, cord blood antibodies against other P. falciparum proteins were not predictive of this reduced rate of severe infection.

In addition, Kurtis and colleagues vaccinated female mice with the analogous Plasmodium berghei Schizont Egress Antigen-1 (PbSEA-1) before mating them and infecting their offspring with P. berghei. Pups whose mothers had been vaccinated with PbSEA-1 lived 32-67% longer than those whose mothers had not been vaccinated. Furthermore, 40% of the pups with vaccinated mothers completely cleared the infection.

In summary, the team in Tanzania found that cord blood anti-PfSEA-1 was predictive of a reduced risk of severe malarial infection during the first 12 months of life. Their vaccination study in mice suggests that immunity to SEA-1 may reduce the severity of malarial infection.

COMMENTARY

In 2017, Plasmodium falciparum caused nearly 219 million cases of malaria and nearly 435,000 deaths. Children younger than 5 years of age were by far the most vulnerable, accounting for 61% of all malarial fatalities (primarily in sub-Saharan Africa). Despite continued efforts and increased funding, the extent of mortality plateaued during the preceding three years and did not continue the steady decline noted earlier this millennium.1

Although malaria is especially problematic for young children, infants are relatively spared from malaria during the first six months of life. Even most congenitally infected newborns clear their infection without adverse consequences. Nonetheless, some newborns become sick with malaria and die, and placental and congenital malaria have been associated with increased anemia and clinical malaria after the first few months of life.2 It is not clear why some infected newborns and young infants get sick with malaria and others seem to be protected; further research with the PfSEA-1 antibodies might yield clues.

For prevention of malaria, development of a vaccine has proven difficult. P. falciparum exhibits wide antigenic variation and mutates quickly, as exemplified by its rapid resistance to many antimalarial drugs. Furthermore, P. falciparum encodes approximately 5,300 genes, providing a wide range of potential vaccine targets. Most importantly, the complexity of the malarial life cycle adds a unique set of challenges.3

The life cycle of P. falciparum in humans can be divided into three stages: the infectious pre-erythrocyte stage, the symptomatic erythrocyte stage, and the transmitting gametocyte stage.3 While vaccines targeting the first stage have the potential to prevent disease formation all together, they have no true correlate in natural malarial immunity. In contrast, vaccines targeted to the second stage seem to mimic the process of natural immunity, but delay immune activation until after infection and possible symptom development. The third stage has produced less interest, as immunization targeting this stage would provide no direct immunity to the already symptomatic individual.3

The RTS vaccine was an attempt to target the first stage of P. falciparum’s life cycle in humans. Briefly, the RTS vaccine consists of a truncated circumsporozoite protein (CSP) fused to hepatitis B surface antigen.4 It was intended to boost immunity before P. falciparum invades erythrocytes and children begin showing symptoms. This vaccine has been the most successful malarial vaccine to date, proving effective at inducing complement-fixing antibodies and leading to a 36.3% average rate of protection against clinical malaria during the first 48 months.4,5

Unfortunately, this limited protection wanes quickly, and the vaccine has limited efficacy in children with prior malaria exposure. Specifically, after seven years of follow-up, the RTS vaccine was determined to have a 4.4% average rate of protection.5 At four years post-vaccination, its efficacy was near zero, and by five years, it actually showed negative efficacy, especially in children with higher malaria exposure.5 This reduction in efficacy is paralleled by the rapid decay in functional antibodies that became nearly undetectable at 8.5 months post-vaccination.4

It is hypothesized that while the RTS provides early protection against malaria sporozoite infection, it delays development of immunity to blood-stage parasites, increasing the risk of later infection.5 Furthermore, children who already have been exposed to malaria at the time of vaccination show reduced antibody induction. Interestingly, these children also had higher levels of antibodies to blood-stage antigens compared with children who had lower malarial exposure.4

It is possible that a vaccine targeting blood-stage antigens may prove more efficacious against P. falciparum. In 2014, Kurtis and colleagues discovered that antibodies against PfSEA-1, an antigen expressed on Schizont-infected erythrocytes, impaired parasite replication during the blood-stage of infection.6 In addition, African adolescents and adults with anti-PfSEA-1 had lower parasite burden, and children with these antibodies did not experience episodes of severe malaria.6

The new work by Kurtis and colleagues provides additional support to the notion that immune response to PfSEA-1 may reduce the severity of malarial infection. Specifically, transplacental anti-PfSEA-1 was associated with a reduction in risk of severe malarial infection after birth and even into the high-risk period after six months, when levels of maternal antibodies are rapidly declining. The results of Kurtis’ experiment in mice suggest that immunity to this antigen alone may provide protection, bolstering hope for future vaccine development.

While a PfSEA-1 vaccination may fall prey to the same waning effects as RTS, it is possible that its mimicry of the natural immune response to blood-stage parasites may show improved longevity. And, blocking just the symptom-producing blood stage could allow children to develop their own natural immunity to the pre-erythrocytic stages of infection. Future research also should examine the effects of anti-PfSEA-1 after 12 months when maternal IgG has completely disappeared, as well as the efficacy of PfSEA-1 vaccination in humans.

REFERENCES

  1. World Health Organization. Malaria. Available at: https://www.who.int/malaria/en/. Accessed May 27, 2019.
  2. Hartman TK, Rogerson SJ, Fischer PR. The impact of maternal malaria on newborns. Ann Trop Paediatr 2010;30:271-282.
  3. Crompton PD, Pierce SK, Miller LH. Advances and challenges in malaria vaccine development. J Clin Invest 2010;120:4168-4178.
  4. Kurtovic L, Agius PA, Feng G, et al. Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure. BMC Med 2019;17:45.
  5. Olotu A, Fegan G, Wambua J, et al. Seven-year efficacy of RTS, S/AS01 malaria vaccine among young African children. N Engl J Med 2016;274:2519-2529.
  6. Raj DK, Nixon CP, Nixon CE, et al. Antibodies to PfSEA-1 block parasite egress from RBCs and protect against malaria infection. Science 2014;344:871-877.